Dosing regimen

The dosing regimen for epineprin

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Adjunvtive vasopressors
The following drugs can be added to vasopressor therapy with catecholamines in selected
situations
Vasopressin
Antidiuretic hormone (adh) is an osmoregulatory hormone that is also called vasopressin because
it produces vasoconstriction
Actions
The vasoconstrictor effect of vasopressin are mediated by specialized vasopressin (v1) reseptors
located on vascular smooth muscle. Vasoconstriction is most prominent in skin, skeletal muscle,
and splanchnic circulation (19). Exogenous vasopressin does not increase blood pressure in
healthy volunteers, but it can produce significant increases in blood pressure in patients with
hypertension caused by peripheral vasodilation (19). This tipe of hypotension occurs in septic
shock, anaphylactic shock, autonomic insufficiency and the hypotension associated with spinal
and general anesthesia.
Other actions of vasopression include enhanced water reabsorption in the distal renal tubules
(mediated by v2 receptors) and stimulation of ACTH release by the anterior pituitary gland
(mediated by v3 receptors). These actions are clinically silent when vasopressin is administered
in the recommended doses (19)

Clinical uses
Vasopressin can be used in the following clinical situations
1. In the resuscitation of cardiac arrest, vasopressin can be given as a single IV dose (40
units) to replace the first or second dose of epinephrine
2. In cases of septic shock that are resistant, or refractory to hemodynamic support with
noreepinephrine or dopamine, a vasopressin infusion can be used to raise the blood
pressure and reduce the catecholamine requirement (catecholamine sparing effect).
Unfortunately, there is no survival benefit associated with the this practice
3. In cases of hemorrhage from esophageal or gastric varices, vasopressin infusions can be
used to promote splanchnic vasoconstriction and reduce the rate of bleeding
Dosing regimen
The plasma half-life of exogenous vasopressin is 5-20 min, so vasopressin must be given by
continuous infusion tu produce prolonged effects.
In septic shock the recommended infusion rate is 0,01-0,04 units/hr, and a rate of 0,03 units/hr is
most popular
Adverse effects
Adverse effects are uncommon with infusion rate <0,04 units/hr. at higher infusion rates,
unwanted effects can include consequences of excessive vasoconstriction (e.g. impaired renal
and hepatic function), along with excessive water retention and hyponatremia.
Terlipressin
Terlipressin is vasopressin analogue that has two advantages over vasopressin. First, it is a
selective v1 receptor agonist, and does not produce the side effects associated with stimulation of
the other vasopressin receptors. Secondly, terlipressin has a much longer duration of

Antiplateles effects
Nitrates inhibit platelet aggregation and nitric oncade is believed to mediate this effect as well.
Because platelet thrombi play an important in the pathogenesis of acute coronary syndromes.
The antiplatelet actions of nitroglycerin have been proposed as the mechanism for the antianginal
effect of the drug. This would explain why nitroglycerins ability to relieve ischemic chest pain is
not shared by other vasodilator drugs.
Clinical uses
Nitroglycerin infusions are used to relieve chest pain in patients with unstable angina and to
augment cardiac output in patients with decompensated heart failure
Dosage and administration
Nitroglycerin binds to soft plastics such as as polyvinylchloride (pvc) which is a common
constituent of the plastics bags and tubing used for intravenous infusions. As much as 80% of the
drug can be lost by adsorptions to pvc in standart intravenous infusion systems. Nitroglycerin
does not bind to glass or hard plastics like polyethylene (pet), so drug loss via adsorption can be
eliminated by using glass bottles and PET tubing. Drug manufacturers often provide specialized
infusion sets to prevent nitroglycerin loss via adsorption
Dosing regiment

When nitroglycerin adsorption is not problem, the initial rate is typically 5-10 mcg/min, which
can be increased in increments of 5-10 mcg/min every 5 minutes until the desired effect is
achieved. The effective dose is 5-100mcg/min in most cases, and infusion rates above
200mcg/min are rarely necessary unless nitrate tolerance has developed.
Adverse effect
The venodilating effect of nitroglycerin can promote hypotension in hypovolemic patients and in
patients with acute right heart failure due to right ventricular infarction. In either of there
conditions, aggressive volume loading is required prior to initiating a nitroglycerin infusion.
Nitroglycerin-induced increases in cerebral blood flow can lead to increased intracranial
pressure, while increases in pulmonary blood flow can result in increased intrapulmonary
shunting and worsening arterial oxygenation in patients with infiltrative lung disease (e.g.
pneumonia or ARDS)
Methemoglobinemia
Nitroglycerin metabolism generates inorganic nitrites, which can oxdize the iron moieties in
hemoglobin to produce methemoglobin. However, clinically apparent methemoglobinemia is not
a common complication of nitroglycerin infusions and occurs only at very high dose rates
Solven toxicity
Nitroglycerin does not readily dissolve in aqueous solutions, and non polar solvents such as
ethanol and propylene glycol are required to keep the drug in solution. These solvents can
accumulate during prolonged infusions. Both ethanol intoxication and propylene glycol toxicity
have been reported as a result of nitroglycerin infusions. Propylene glycol toxicity may be more
common that suspected because this solvent makes up 30-50% of the nitroglycerin preparation.
(for a description of propylene glycol toxicity)
Nitrate tolerance
Tolerance to the vasodilator and antiplatelet actions of nitroglycerin is a well-described
phenomenon and can appear after only 24-48 hours of continuous drug administration. The
underlying mechanism may be oxidative stress-induced endothelial dysfunction. The most
effective measure for preventing or reversing nitrate tolerance is a daily drug-free interval of at
least 6 hours.
Nitroprusside
Nitroprusiside is a rapidly-acting vasodilator that is favored for the treatment of hypertensive
emergencies. The populary of this drug is limited by the risk of cyanide intoxication
Actions

The vasodilator actions of nitroprusside, like those of nitroglycerin, are mediated by nitric axide.
The nitroprusside molecule contains one nitrosyl group (no), which is released as nitric oxide
when nitroprusside enters the bloodstream. The nitric oxide somehow ends up in endothelial
cells. Where it proceeds as shows in figure 533
Like nitroglycerin, nitroprusside dilates both arteries and veins, but it is less potent that
nitroglycerin as a venodilator, and more potent as an arterial vasodilator. Nitroprusside has
variable effect on cardiac output in subjects with normal cardiac function, but consistently
improves cardiac output in patients with decompensated heart failure.
Clinical uses
The principal uses of nitroprusside are the treatment of hypertensive emergencies, where rapid
blood pressure reduction is desirable and management of acute, decomperisated heart failure, as
described on page 248
Dosing regiment
Nitroprusside infusions are started at 0,2mcg/kg/min, and then titrated upward every 5 minutes to
the desire result. Control of hypertension usually requires infusion rates 2-5mcg/kg/min, but
infusion rate should be kept below 3mcg/kg/min, if possible, to limit the risk of cyanide
intoxication. In renal failure, the infustion rate shoul be kept below 1mcg/kg/min to limit
thiocynate accumulation
Cyanide intoxication
Nitroprusside infusions carry a considerable risk of cyanide intoxication. In fact, cyanide
accumulation is common during therapeutic infusion of nitroprusside. The origin of the cyanide
is the nitroprusside molecule, which is a ferricyanide complex with 5 cyanide molecules bound
to an oxidized iron core. This cyanide is released in the bloodstream when nitroprusside breaks
up to release nitric oxide and exert its vasodilator actions. The clearance mechanisms for the
released cyanide are shown in figure 534. Two chemical reactions help to remove cyanide from
the bloodstream. One involves the binding of cyanide to the oxidized iron moiety in
methemoglobin. The other reaction involves the transfer of sulfur from a donor molecul
(thiosulfate) to cyanide to form a thiocyanate compound, which is then cleared by the kidneys.
The latter (transulfuration) reaction is the principal mechanism for removing cyanide from the
human body.
Healthy adults have enough methemoglobin to bind the cyanide in 18mg of nitroprusside, and
enough thiosulfate to bind the cyanide in 50mg of nitroprusside. This means that healthy adults
can detoxify 68mg of nitroprusside. At a nitroprusside infusion rate of 2mcg/kg/minute
(therapeutic dose) in an 80-kg adults, the 68 mg limit of detoxification is reached in 500minutes
(8,3 hr) after the start of the infusion. Thereafter, the cyanide released by nitroprusside will

combine with the oxidened iron in cytochrome oxidase and block the utilization of oxygen in the
mitochondria
The capacity for cyanide removal is reduced by thiosulfate depletion, which is common in
smoker and postoperative patients. The eliminate the risk of thiosulfate depletion, thiosulfate can
be routinely added to the nitroprusside infusate. About 500mg of thiosulfate should be added for
every 50mg of nitroprusside
Clinical manifestations
One of the early signs of cyanide accumulations is nitroprusside tachiphylaxis. Progressively
increasing requirements for nitroprusside to maintain the desired blood pressure. Sign of
impaired oxygen utilization (i.e an increasein central venous 02 saturation, and an increase in
plasma lactate levels) often do not appear until the late stages of cyanide intoxication. As the
result, the absence of lactic acidosis during nitroprusside infusion does not exclude the
possibility of cyanide accumulation
Evidence of possible cyanide intoxication should prompt immediate discontinuation of
nitroprusside. Whole blood cyanide levels can be used to confirm the diagnosis of cyanide
intoxication, but result are not immediately available, and clinical suspicion is the impetus to
begin detoxification measures. These measures are are described in chapter 55
Thiocyanate intoxication
The most important mechanism for cyanide removal is the formation of thiocyanate, which is
slowly excreated in the urine. When renal function is impaired, thiocyanate can accumulate and
produce a toxic syndrome that is distinct from cyanide intoxication. The clinical fetures of
thiocyanate intoxication include anxiety, confusion, papillary constriction, tinnitus,
hallucinations, and generalized seizures. Thiocyanate can also promote hypothyroidism by
blocking thyroidal uptake of iodine.
The diagnosis of thiocyanate toxicity is established by the serum thiocyanate level. Normal
levels are below 10mg/L and clinical toxicity is usually accompanied by levels above 100mg/L.
thiocyanate intoxication can be treated by hemodialysis or peritoneal dialysis
A final word
The vasopressor folly
One of the frustrating aspects of critical care practice is the continuing high mortality rates in
circulatory shock. Particularly septic shock, despite correction of the blood pressure with
vasopressor drugs. The likely explanation for this is the probability that low blood pressure plays
little or not role in the pathogenesis of circulatory shock, or in the clinical outcomes. This is
consistent with observations in septic shock indicating that the pathological injury is a defect in

oxygen utilization in mitochondria, and the culprit is uncontrolled inflammation, not a low blood
pressure. In light of this explanation, the decrease in blood pressure that occurs in shock is more
likely to be the result of the pathological cell injury (i.e, shock of the blood levels) rather that a
cause of the injury. Hypotension then becomes one of several consequences of the cellular shock,
and the correcting the hypotension is not expected to correct the primary pathological process.
After at least 50 years of focusing on vasopressor therapy in shock, its time for a do-over.