G7i / 23A20: Compare and contrast the relevant pharmacology of intravenous adrenaline andvasopressin

23A20: Exam Report

Compare and contrast the relevant pharmacology of intravenous adrenaline and vasopressin

20% of candidates passed this question.

The major emphasis of this question and opportunity to score marks reside in “comparing the two drugs” in various aspects – pharmaceutics, indication, mechanism of action, pharmacodynamics, and pharmacokinetics. Although most of the candidates were able to list pharmaceutics, indications, kinetics and dynamics of both the drugs in reasonably structured and tabulated format, many failed to highlight the important commonalities and differences between the two. In mechanism of action, details of the receptor, their location and second messenger system were expected.

In pharmacodynamics, similarities and differences in cardiovascular, respiratory, haematological, renal and metabolic effects were needed. There are additional neurological effects and genito-urinary (tocolysis and sphincter tone) of adrenaline which were rarely mentioned.

There were frequent significant omissions or incorrect details in the pharmacokinetics sections of both drugs.

G7i / 23A20: Compare and contrast the relevant pharmacology of intravenous adrenaline and vasopressin

Adrenaline

Vasopressin

Pharmaceutics

Both naturally occurring and can be given via IV. Different units/ml

Adrenaline

Naturally-occurring catecholamine

IV – 0.1/1 mg/ml clear, colourless of adrenaline hydrochloride

Vasopressin

Naturally-occurring nonapeptide hormone

IV argipressin – clear, colourless solution 20 units/ml

Indication

Both can be used as a vasoactive agents but have other different indications

Adrenaline

Asystole, cardiac arrest

Anaphylaxis, with/without shock

Low cardiac output states

Vasopressin

Catecholamine-refractory septic shock
Management of cranial diabetes insipidus
Management of bleeding oesophageal varices
Perioperative/traumatic management of Haemophiliac patients and von Willebrand’s disease

Pharmaceutics

Both naturally occurring and can be given via IV. Different units/ml

Adrenaline

Naturally-occurring catecholamine

IV – 0.1/1 mg/ml clear, colourless of adrenaline hydrochloride

Vasopressin

Naturally-occurring nonapeptide hormone

IV argipressin – clear, colourless solution 20 units/ml

Mechanism of Action

Both drugs have multiple target receptor sites which utilises G-protein coupled receptors.
Location of receptors are different.

Adrenaline

Directly acting, natural sympathomimetic amine that has equal activity at both alpha and beta adrenoceptors.

B1 (Gs coupled protein receptors):

  • Predominantly heart, kidney and fat cells
  • Increases activity of adenylate cyclase, increases cAMP from ATP -> Protein Kinase A which phosphorylates calcium channels and myosin light chains

B2 (Gs also)

  • Predominantly in airway smooth muscles but also exists on cardiac muscles, uterine muscles, alveolar type 2 cells, mast cells, mucous glands, epithelial cells, vascular endothelium, eosinophils, lymphocytes and skeletal muscles
  • Increases activity of adenylate cyclase as above

A1 (Gq coupled protein receptors):

  • Predominantly found on vascular smooth muscle
  • Activation of phospholipase C, increasing IP3 (releases Ca from endoplasmic reticulum and DAG (activates protein C)

Vasopressin

Directly acting. IV argipressin predominantly acts at V1 receptors.

V1 (Gq coupled protein receptor)

  • Vascular smooth muscle, platelets and myometrium
  • Increases activity of phospholipase C, increasing IP3 and DAG,

V2 (Gs coupled protein receptor)

  • Distal renal tubule and collecting ducts
  • Activation leads to aquaporin-2 trafficking from intracellular vesicle membranes into the apical cell membrane, allowing water reabsorption.
  • Also present on endothelial cells, with activation leading to vwF release

V3 (Gq coupled protein receptor)

  • Pituitary, contributing to ACTH release.

Dosages

Different measurement units.
Vasopressin must be administered via CVC while adrenaline can be given peripherally.

Adrenaline

0.1 – 1 mg bolus

0.02 – 0.3 mcg/kg/min – IV infusion

Vasopressin

Treatment of central DI – 5-20 units SC/IM every 4 hours

Bleeding varices – 20 units IV over 15 minutes

Catecholamine-refractory septic shock – 0.01-0.04 units/min

Pharmacodynamics

Both increase mean arterial pressure, but otherwise significantly different effects

CVS

Adrenaline

Positive inotrope, chronotrope

HR increases, arrhythmogenic

CO increases

Myocardial oxygen consumption increases

Vasopressin

Increase in mean arterial pressure and systemic vascular resistance.

Significant reduction in cutaneous & splanchnic perfusion

Resp

Adrenaline

Potent bronchodilator

Increases viscosity of bronchial secretions

Vasopressin

Vasodilation in the pulmonary artery in hypoxic and physiological conditions

CNS

Adrenaline

Weak mydriatic effects when applied topically to the eye

CNS excitation

Vasopressin

GIT

Adrenaline

Decreases intestinal tone and secretions

Splanchnic blood flow increases

Vasopressin

Renal

Adrenaline

Positive inotrope, chronotrope

HR increases, arrhythmogenic

CO increases

Myocardial oxygen consumption increases

Vasopressin

Reduction in urine output in patients with cranial diabetes inspidius

Genitourinary

Adrenaline

Tocolysis in pregnancy

Bladder tone decreased

Sphincter tone increased, leading to difficulty with micturition

Vasopressin

Metabolism / Other

Adrenaline

Decreases insulin secretion, increases glucagon secretion and rate of glycogenolysis

Plasma FFA levels increased

Vasopressin

Increase in vWF and factor VIII

Toxicity

Adrenaline

Tachycardia, dysrhythmias, myocardial ischemia, CNS excitation.

Necrosis with extravasation.

Necrosis when administered in regions of body supplied by end arteries.

Vasopressin

Mesenteric ischemia

Ischemia of peripheral limbs

Pharmacokinetics

Neither are significantly protein bound. Both have different metabolism. Vasopressin is predominantly renally excreted unchanged.

A

Adrenaline

IV –100% bioavailability

Vasopressin

IV – 100% bioavailability

D

Adrenaline

Minimally bound to serum proteins

Stays in plasma, Vd < 0.05L/kg

Vasopressin

Not-protein bound

Vd 0.14 L/kg

M

Adrenaline

Catechol-O-methyltransferase and Monoamine oxidase

Inactive metabolites

Vasopressin

Endogenous vasopressin metabolised to vasopressinases into amino acids

Argipressin – 35% of administered dose undergoes enzymatic metabolism

E

Adrenaline

Predominantly renally cleared

Vasopressin

65% administered dose of argipressin excreted unchanged in the urine

Author: Michael Wu