Inotropes and vasoconstrictors

Question 1

What are inodilators?

Answer 1

Drugs that enhance adrenergic activity through phosphodiesterase (PDE) inhibition.

Beta stimulation results in increased intreacellular cAMP but within an hour, excess B stimulation leads to decoupling from the second messenger system and cAMP production is reduced.

PDE III is responsible for the breakdown of cAMP and can be inhibited by milrinone and exoximone. Therefore these drugs can enhance and restore beta adreonreceptor function.

In trials, 20% increase in mortality when used for heart failure.

Question 2

Milrinone

Answer 2

Most effective of the PDE inhibitors because it also binds to the calcium release channels on te SR.

Half life is 2-3 hours and doubled in renal failure.

Drug of choice in patients with heart failure who have a degree of diastolic dysfunction, right sided failure or pulmonary hypertension.

Hypotension is the most common problem, esp with the loading dose. Noradrenaline often given concurrently.

Question 3

Levosimendan

Answer 3

Inodilator. Primary action is as a calcium sensitiser within the myocardium. Binds to calcium-saturated troponin C and stabilises the complex, inhibiting troponin I effects. Facilitates actin-myosin crossbridge formation and improves myocardial contraction.

During diastole, when intracellular calcium concentrations are reduced, levosimendan dissociates from troponin C and relaxation is unimpeded. Main metabolite has similar action so an infusion can last for days.

Also vasodilating as an antagonist of the ATP-associated K+ channel and a PDE III inhibitor

Question 4

Vasopressin

Answer 4

AKA arginine vasopressin and ADH. Differs from oxytocin by only 2 amino acids.

Hypovolaemic shock: increases markedly
Osmo increase: increases in step
Blood volume reduces there is little effect until about 10% of blood volume is lost then it increases exponentially.

Desmopressin: substitute arginine for dextro-arginine which slows its enzymatic destruction and deaminating the terminal cysteine affects receptor affinity

Terlipressan: slowed breakdown which cleaved glycine tail

Question 5

Vasopressin 1

Answer 5

Vasoconstriction, esp in the gut, skin and skeletal muscle and platelet aggregation

Question 6

Vasopressin 2

Answer 6

Opens aquaporin channels in collecting ducts and releases von Willebrand factor

Question 7

Vasopressin 3

Answer 7

Mainly CNS activity including ACTH release

Question 8

Vasopressin use in therapeutic vasoconstriction:

Answer 8

Vaso, esp terlipressin, used in the management of bleeding from oesophageal varices. Portal venous pressure is reduced by splanchnic vasoconstriction.

Vasoconstriction of choice in patients with pulmonary HTN (NA increases pulmonary vascular resistance).

0.5-1units/hr

Question 9

Hydrocortisone

Answer 9

The hypertensive effect of alpha 1 stimulation fades in sepsis and other shock conditions. Low dose (50mg) hydrocortisone has been shown to improve responsiveness to alpa 1 agonists. Better when given with vasopressin > NA. 4x day for sepsis.

Question 10

Methylene blue

Answer 10

Neither an inotrope nor vasoconstrictor but can restore vascular tone in some circumstances.

Hypotension in sepsis is associated with excess inducible nitric oxide synthase. The second messenger in nitric oxide vasodilation is guanylate cyclase and that is inhibited by methylene blue.

1-1.5 mg/kg has been associated with increased vascular tone in sepsis and in cases of vasoplegia after cardiopulmonary bypass, but its use is also associated with adverse effects.

Discolouration of skin and urine is temporary, but paradoxically, given that it is a treatment for methaemoglobinaemia, doses in excess of 4 mg/kg have caused methaemoglobinaemia. Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) deficiency are particularly vulnerable to this effect. Pulse oximeters can report falsely low oxygen saturation, but pulmonary vasoconstriction and true desaturation have also been reported.