Vasopressin is used:
1. in the management of cranial diabetes insipidus
2. in the management of bleeding oesophageal varices
3. in the perioperative/trauma management of patients with haemophilia and von Willebrand’s disease
4. in the management of polyuria and polydipsia post-hypophysectomy and
5. in the management of catecholamine-refractory septic shock.
Vasopressin is a naturally occurring nonapeptide prohormone synthesized in the paraventricular and supraoptic nuclei of the posterior hypothalamus. It is also available in three synthetic analogue forms: 8-arginine-vasopressin (argipressin) which is identical to endogenous human vasopressin; triglycyl-lysine-vasopressin (terlipressin/glypressin) which is a pro-drug requiring cleavage of three glycyl residues to form lysine-vasopressin which is found in pigs; and 1-deamino-8-O-arginine-vasopressin (desmopressin).
Argipressin is available as a clear, colourless solution in a glass ampoule containing 1 ml of argipressin for subcutaneous, intravenous, or intramuscular injection in a concentration of 20 IU/ml (= 0.4 mg argipressin). Terlipressin/glypressin is available as terlipressin acetate as a clear, colourless solution for intravenous administration in a concentration of either 0.12 mg/ml or 0.2 mg/ml. Terlipressin is also available as a white powder containing 1 mg of terlipressin acetate such that, when reconstituted in the provided 5 ml of solvent, 1 ml of solution contains 0.2 mg of the drug. Desmopressin is available as an oral lyophilizate containing 60, 120, and 240 micrograms of desmopressin acetate; as tablets containing 0.1 and 0.2 mg of desmopressin acetate; as a clear, colourless 1 ml solution containing 4 micrograms of desmopressin acetate; and as an aqueous solution for intranasal administration containing 0.01% w/v of the drug.
Mode of action
Endogenous vasopressin (or ADH) and its synthetic analogues act via G-protein vasopressin receptors V1, V2, and V3, and also has affinity for oxytocin-type receptors. V1 receptors are present in vascular smooth muscle, platelets, and myometrium. Activation of V1 receptors leads to increased intracellular calcium concentrations and vasoconstriction. V2 receptors are found in the distal renal tubule and collecting ducts, and activation leads to aquaporin-2 trafficking from intracellular vesicle membranes within renal epithelial cells into the apical cell membrane, allowing water reabsorption. V2 receptors are also present on endothelial cells, allowing von Willebrand factor (vWF) release that prevents the breakdown of factor VIII in plasma. V3 receptors are found in the pituitary and contribute to ACTH release. Oxytocin-type receptors are present on vascular smooth muscle and the myometrium, and activation results in increased NO synthase activity leading to vasodilation. Desmopressin has ten times the antidiuretic action of endogenous vasopressin, but 1500 times less vasoconstriction effect.
Vasopressin can be administered subcutaneously, intramuscularly, intravenously, intranasally, orally, and via a sublingual route, depending on the synthetic vasopressin analogue being used. Argipressin is used in the treatment of cranial diabetes insipidus at a dose of 5–20 units subcutaneously or intramuscularly every 4 hours. In the management of bleeding varices, 20 units are administered by intravenous infusion over 15 minutes. It may also be used in the management of catecholamine-refractory septic shock by continuous infusion via a central venous catheter at a rate of 0.01–0.04 units/min. Terlipressin/glypressin is used in the management of bleeding varices, with a 2 mg dose being administered intravenously every 4 hours for a maximum of 48 hours. Desmopressin is used in the management of cranial diabetes insipidus and post-hypophysectomy polyuria/polydipsia. An initial dose of 60 micrograms sublingually, or 0.1 mg orally three times daily, is recommended. The dose should then be modified according to the clinical response. The drug may also be given intravenously, intramuscularly, or subcutaneously in the treatment of cranial diabetes insipidus at a dose of 1–4 micrograms once daily. Desmopressin may be given by intravenous infusion at a dose of 0.4 micrograms/kg in the perioperative or trauma management of patients with haemophilia or von Willebrand’s disease.
In the presence of shock, vasopressin causes an increase in the mean arterial pressure and systemic vascular resistance via its vasoconstrictor effect. At very low concentrations, vasopressin causes vasodilatation in certain vascular beds in animal models. It causes vasodilatation of the pulmonary artery in hypoxic and physiological conditions.
A reduction in the urine output and resolution of polydipsia are seen, following administration of the drug to patients with cranial diabetes insipidus.
Due to the vasoconstriction effect of vasopressin (and other catecholamines if concurrently administered), a significant reduction in cutaneous and splanchnic perfusion may occur.
Desmopressin is the only synthetic analogue that may be administered by an oral, sublingual, or nasal route. 0.25% of a sublingual dose is absorbed; oral administration results in 0.08–0.16% of a dose being absorbed; 10% of an administered intranasal dose is absorbed.
Argipressin is not protein-bound. It has a VD of 0.14 l/kg. The VD of terlipressin/glypressin is 0.5 l/kg and has a biphasic plasma level curve, suggesting a two-compartment pharmacokinetic model. The VD of Desmopressin is 0.2–0.32 l/kg.
Endogenous vasopressin is metabolized by vasopressinases and has a half-life of 10–35 minutes. Argipressin has a half-life of 10–20 minutes, and 35% of an administered dose undergoes enzymatic metabolism. Terlipressin/glypressin has a half-life of 50–70 minutes. Desmopressin undergoes minimal hepatic metabolism and has a half-life of 2–3 hours.
As a lyophilized powder (containing citric acid monohydrate (20.75 mg), disodium hydrogen phosphate dihydrate (16.25 mg), mannitol (170 mg), sodium hydroxide or phosphoric acid) which is diluted in water prior to use to yield a clear, colourless, isotonic solution containing 2 mg/ml of vecuronium bromide. Mannitol is used to alter the tonicity, and the presence of either sodium hydroxide or phosphoric acid adjusts the pH to 4. The solution is stable for 24 hours.
Mode of action
Vecuronium acts by competitive antagonism of acetylcholine at nicotinic (N2) receptors at the post-synaptic membrane of the neuromuscular junction. The drug also has some pre-junctional action.
Routes of administration/doses
The drug is administered intravenously. The ED90 of vecuronium is estimated to be 0.057 mg/kg. An initial dose of 0.08–0.1 mg/kg is recommended, providing muscle relaxation for between 25 and 40 minutes. Endotracheal intubation can be achieved within 90–120 seconds of an intravenous dose, with maximal resultant neuromuscular blockade achieved within 3–5 minutes following administration. Ninety-five percent recovery of the twitch height occurs within approximately 45 minutes. Maintenance of neuromuscular blockade may be achieved with bolus doses of 0.02–0.03 mg/kg. Vecuronium may be administered by intravenous infusion at a rate of 0.8–1.4 micrograms/kg/min. The drug is non-cumulative with repeated administration.
Vecuronium has minimal cardiovascular effects; with large doses, a slight (9%) increase in the cardiac output and 12% decrease in the systemic vascular resistance may occur. Unlike pancuronium, the drug will not antagonize the haemodynamic changes or known side effects produced by other pharmaceutical agents or surgical factors.
Neuromuscular blockade leads to apnoea. Vecuronium has a very low potential for histamine release; bronchospasm is extremely uncommon.
There have been rare reports of fatal anaphylactoid reactions with the administration of vecuronium. Cross-sensitivity may exist with rocuronium and pancuronium.
The drug is 60–90% protein-bound in the plasma. The VD is 0.18–0.27 l/kg. The drug does not cross the blood–brain barrier. Very small amounts of vecuronium may cross the placenta, but not in clinically significant doses.
Vecuronium is metabolized by deacetylation in the liver to the active metabolites 3- and 17-hydroxy and 3,17-dihydroxyvecuronium. These metabolites, which, in the case of 3-hydroxyvecuronium, may have up to 50% of the potency of vecuronium, are present in very low concentrations, although they may be of clinical significance after prolonged dosing.
25–30% of the dose is excreted unchanged in the urine, and 20% unchanged in the bile. Metabolized drug is excreted in the bile. The clearance is 3–6.4 ml/kg/min, and the elimination half-life is 31–80 minutes. Renal failure leads to a prolongation of the elimination half-life, but to no clinically significant increase in the duration of action of vecuronium. Hepatic failure may cause a significant dose-dependent decrease in the clearance, and consequent increase in the duration of action, of the drug.
The duration of action of vecuronium, in common with other non-depolarizing relaxants, is prolonged by hypokalaemia, hypocalcaemia, hypermagnesaemia, hypoproteinaemia, dehydration, acidosis, and hypercapnia. The following drugs, when co-administered with vecuronium, increase the effect of the latter: volatile anaesthetic agents, induction agents (including ketamine), fentanyl, suxamethonium, diuretics, calcium channel blockers, alpha- and beta-adrenergic antagonists, protamine, lidocaine, metronidazole, and the aminoglycoside antibiotics. Patients with burns may develop resistance to the effect of vecuronium. Onset of neuromuscular blockade is likely to be lengthened and the duration of action shortened in patients receiving chronic anticonvulsant therapy. The use of vecuronium appears to be safe in patients susceptible to malignant hyperpyrexia.
Reversal of neuromuscular-blocking activity by vecuronium may be achieved using neostigmine (in combination with glycopyrronium), but only after four twitches have returned on the train-of-four count. The gamma-cyclodextrin sugammadex may be used to reverse vecuronium-induced neuromuscular blockade by encapsulating vecuronium molecules within the plasma, thereby creating a concentration gradient favouring the movement of remaining vecuronium molecules from the neuromuscular junction back into the plasma.
Verapamil is used in the treatment of:
1. hypertension of mild to moderate severity
2. angina and
3. paroxysmal supraventricular tachycardia, and atrial fibrillation and flutter.
As 40/80/120/160/180/240 mg tablets and as a clear solution for injection of a racemic mixture of verapamil hydrochloride containing 2.5 mg/ml.
Mode of action
Verapamil causes competitive blockade of cell membrane slow Ca2+ channels, leading to a decreased influx of Ca2+ into vascular smooth muscle and myocardial cells. This results in electromechanical decoupling and inhibition of contraction and relaxation of cardiac and smooth muscle fibres, leading to coronary and systemic arterial vasodilation.
Routes of administration/doses
The adult oral dose is 240–480 mg daily in 2–3 divided doses. The corresponding intravenous dose in 5–10 mg, administered over 30 seconds; the injection should cease as soon as the desired effect is achieved. The peak effect after intravenous administration occurs at 3–5 minutes, and the duration of action is 10–20 minutes.
Verapamil is a class IV antiarrhythmic agent; it decreases automaticity and conduction velocity, and increases the refractory period. AV conduction is slowed; the drug appears to be taken up and bound specifically by AV nodal tissue. The drug causes a decrease in the systemic vascular resistance and is a potent coronary artery vasodilator. Verapamil has negative dromotropic and inotropic effects which are enhanced by acidosis.
Oral administration of the drug may lead to dizziness, flushing, nausea, and first- or second-degree heart block. Intravenous administration may precipitate heart failure in patients with impaired left ventricular function and precipitate ventricular tachycardia or fibrillation in patients with Wolff–Parkinson–White syndrome.
Verapamil is completely absorbed when administered orally; the bioavailability is 10–22% due to a significant first-pass.
Occurs by demethylation and dealkylation in the liver; the metabolites possess some activity.
The effects of volatile agents and beta-adrenergic antagonists on myocardial contractility and conduction are synergistic with those of verapamil; caution should be exercised when these combinations are used. The drug increases the serum concentrations of co-administered digoxin.
Verapamil and dantrolene administered concurrently in animals cause hyperkalaemia, leading to ventricular fibrillation; these drugs are not recommended for use together in man. The drug decreases the MAC of halothane in animal models; chronic exposure to the drug may potentiate the actions of both depolarizing and non-depolarizing relaxants. Verapamil attenuates the pressor response to laryngoscopy and intubation.
Verapamil is not removed by haemodialysis.