Adrenalin Chloride
DESCRIPTION
A sterile solution intended for subcutaneous or intramuscular injection. When diluted, it may also be administered intracardially or intravenously. Each milliliter contains 1 mg Adrenalin (epinephrine) as the hydrochloride dissolved in Water for Injection, USP, with sodium chloride added for isotonicity. The ampoules contain not more than 0.1% sodium bisulfite as an antioxidant, and the air in the ampoule has been displaced by nitrogen. The Steri-Vials(r) contain 0.5% Chlorobutanol (chloroform derivative) as a preservative and not more than 0.15% sodium bisulfite as an antioxidant. Epinephrine is the active principle of the adrenal medulla, chemically described as (--)-3,4-Dihydroxy-alpha-[(methylamino) methyl] benzyl alcohol, and has the following structural formula:
CLINICAL PHARMACOLOGY
Adrenalin (epinephrine) is a sympathomimetic drug. It activates an adrenergic receptive mechanism on effector cells and imitates all actions of the sympathetic nervous system except those on the arteries of the face and sweat glands. Epinephrine acts on both alpha and beta receptors and is the most potent alpha receptor activator.
INDICATIONS AND USAGE
In general, the most common uses of epinephrine are to relieve respiratory distress due to bronchospasm, to provide rapid relief of hypersensitivity reactions to drugs and other allergens, and to prolong the action of infiltration anesthetics. Its cardiac effects may be of use in restoring cardiac rhythm in cardiac arrest due to various causes, but it is not used in cardiac failure or in hemorrhagic, traumatic, or cardiogenic shock.
Epinephrine is used as a hemostatic agent. It is also used in treating mucosal congestion of hay fever, rhinitis, and acute sinusitis; to relieve bronchial asthmatic paroxysms; in syncope due to complete heart block or carotid sinus hypersensitivity; for symptomatic relief of serum sickness, urticaria, angioneurotic edema; for resuscitation in cardiac arrest following anesthetic accidents; in simple (open angle) glaucoma; for relaxation of uterine musculature and to inhibit uterine contractions. Epinephrine injection can be utilized to prolong the action of intraspinal and local anesthetics (see CONTRAINDICATIONS section).
CONTRAINDICATIONS
Epinephrine is contraindicated in narrow angle (congestive) glaucoma, shock, during general anesthesia with halogenated hydrocarbons or cyclopropane and in individuals with organic brain damage. Epinephrine is also contraindicated with local anesthesia of certain areas, e.g., fingers, toes, because of the danger of vasoconstriction producing sloughing of tissue; in labor because it may delay the second stage; in cardiac dilatation and coronary insufficiency.
WARNINGS
Administer with caution to elderly people; to those with cardiovascular disease, hypertension, diabetes, or hyperthyroidism; in psychoneurotic individuals; and in pregnancy. Patients with long-standing bronchial asthma and emphysema who have developed degenerative heart disease should be administered the drug with extreme caution. Overdosage or inadvertent intravenous injection of epinephrine may cause cerebrovascular hemorrhage resulting from the sharp rise in blood pressure.
Fatalities may also result from pulmonary edema because of the peripheral constriction and cardiac stimulation produced. Rapidly acting vasodilators, such as nitrites, or alpha blocking agents may counteract the marked pressor effects of epinephrine.
Epinephrine is the preferred treatment for serious allergic or other emergency situations even though this product contains sodium bisulfite, a sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations
PRECAUTIONS
General: Adrenalin (epinephrine injection, USP) should be protected from exposure to light. Do not remove ampoules or syringes from carton until ready to use. The solution should not be used if it is pinkish or darker than slightly yellow or if it contains a precipitate.
Epinephrine is readily destroyed by alkalies and oxidizing agents. In the latter category are oxygen, chlorine, bromine, iodine, permanganates, chromates, nitrites, and salts of easily reducible metals, especially iron.
Drug Interactions: Use of epinephrine with excessive doses of digitalis, mercurial diuretics, or other drugs that sensitize the heart to arrhythmias is not recommended. Anginal pain may be induced when coronary insufficiency is present.
The effects of epinephrine may be potentiated by tricyclic antidepressants; certain antihistamines, e.g., diphenhydramine, tripelennamine, d-chlorpheniramine; and sodium l-thyroxine.
Usage in Pregnancy: Pregnancy Category C. Adrenalin (epinephrine) has been shown to be teratogenic in rats when given in doses about 25 times the human dose. There are no adequate and well-controlled studies in pregnant women. Adrenalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
ADVERSE REACTIONS
Transient and minor side effects of anxiety, headache, fear, and palpitations often occur with therapeutic doses, especially in hyperthyroid individuals. Repeated local injections can result in necrosis at sites of injection from vascular constriction. "Epinephrine-fastness" can occur with prolonged use.
DOSAGE AND ADMINISTRATION
Adrenaline is an endogenous substance that is produced in the adrenal medulla and has important physiological effects. It is also used pharmacologically as a direct-acting sympathomimetic (see <23112-s.htm> <23112-s.htm>). It is a potent agonist at both alpha and beta adrenoceptors, although the effect on beta adrenoceptors is more marked, particularly at lower doses. These properties explain many aspects of its pharmacology, although the consequent reflex compensating responses of the body also have a role in determining its effects.
The major effects of adrenaline are dose-related and include:
increased speed and force of cardiac contraction (with lower doses this causes increased systolic pressure yet reduced diastolic pressure since overall peripheral resistance is lowered, but with higher doses both systolic and diastolic pressure are increased as stimulation of peripheral alpha receptors increases peripheral resistance)
increased blood flow to skeletal muscle (reduced with higher doses); reduced blood flow in the kidneys, mucosa, and skin; little direct effect on cerebral blood flow
relaxation of bronchial smooth muscle
hyperglycaemia and markedly increased oxygen consumption due to metabolic effects
Adrenaline has an important role in the management of acute allergic reactions and can be life-saving in patients with anaphylaxis and anaphylactic shock ( ). It is also used in advanced cardiac life support ( ). Adrenaline has been used in the treatment of acute asthma but more selective drugs are available, and it has no role in the chronic management of asthma ( <9795-a3-1-e.htm> <9795-a3-1-e.htm>). It has been given by nebulisation in severe croup ( <1060-a8-5-j.htm> <1060-a8-5-j.htm>). Adrenaline is used for a number of other indications including the control of minor bleeding from the skin and mucous membranes, in ophthalmology chiefly for the management of open-angle (simple) glaucoma ( <4500-a1-2-d.htm> <4500-a1-2-d.htm>), and also as an adjunct to local anaesthesia ( <7600-a5-d.htm> <7600-a5-d.htm>). Adrenaline was formerly incorporated into creams used in the treatment of rheumatic and muscular disorders, and in rectal preparations used in the treatment of haemorrhoids. Racepinefrine (racemic adrenaline) and racepinefrine hydrochloride have been used for bronchodilatation.
Adrenaline is usually given by intramuscular injection, although it may also be given subcutaneously. In extreme emergencies, where a more rapid effect is required, adrenaline may be given as a dilute solution (1 in 10 000 or 1 in 100 000) by very slow intravenous injection or by slow intravenous infusion. Alternatively, if intravenous access cannot be obtained, it may also be given by the intraosseous (usually into the marrow of the tibia) or endotracheal routes. Adrenaline has sometimes been injected directly in the heart but current guidelines for the management of cardiac emergencies recommend intravenous injection; this may be into a central vein or peripherally, but in the latter case should be followed by 20 mL of intravenous fluid. Adrenaline may also be applied topically or given by inhalation. Aqueous solutions of adrenaline are usually prepared using the acid tartrate or the hydrochloride but the dosage is generally stated in terms of the equivalent content of adrenaline. Adrenaline acid tartrate 1.8 mg or adrenaline hydrochloride 1.2 mg is equivalent to about 1 mg of adrenaline.
The usual dose of adrenaline in anaphylactic shock is 500 micrograms (0.5 mL of a 1 in 1000 solution) by intramuscular injection repeated as necessary every 5 minutes. A dose of 300 micrograms (0.3 mL of a 1 in 1000 solution) may be appropriate for emergency self-administration, for example by autoinjector. The dose for children depends on age and weight, but is usually about 10 micrograms/kg by intramuscular injection. Suitable doses are 50 micrograms for infants under 6 months of age, 120 micrograms for children aged 6 months to 6 years, and 250 micrograms for those aged 6 to 12 years. If autoinjectors are used, a dose of 150 micrograms may be used for children weighing between 15 and 30 kg and 300 micrograms for those weighing over 30 kg. If intravenous administration is required the dose is 500 micrograms for adults and 10 micrograms/kg for children, given as a more dilute 1 in 10 000 solution at a rate of 1 mL (100 micrograms) or less per minute.
In advanced cardiac life support the initial dose of adrenaline for adults is 1 mg intravenously (10 mL of a 1 in 10 000 solution) and this may be repeated as often as every 2 to 3 minutes throughout the resuscitation procedure. The dose for children is 10 micrograms/kg intravenously. Higher intravenous doses have been used in both adults and children for the second and subsequent doses but are no longer generally recommended. Intraosseous doses for adults and children are the same as those used intravenously. Endotracheal doses for adults are 2 to 3 times the intravenous dose; children may be given 100 micrograms/kg.
Adrenaline relaxes the bronchial musculature and has sometimes been injected subcutaneously or intramuscularly in the management of acute asthmatic attacks. However, in general, the use of adrenaline in asthma has been superseded by beta2 agonists, such as salbutamol, which can alleviate bronchospasm with fewer effects on the heart. If adrenaline is to be used, the adult dose is 0.3 to 0.5 mL of a 1 in 1000 aqueous solution (300 to 500 micrograms); children have received 0.01 mL/kg (10 micrograms/kg) to a maximum of 0.5 mL (500 micrograms). Aqueous solutions with an adrenaline content equivalent to 1 in 100 have occasionally been used by inhalation as a spray to alleviate asthmatic attacks; these solutions must never be confused with the weaker strength used for injection. Pressurised aerosols delivering metered doses equivalent to about 160 micrograms to 275 micrograms of adrenaline have also been used; adults have received 1 or 2 metered inhalations repeated, if necessary, after 3 hours.
Adrenaline is frequently added to local anaesthetics to retard diffusion and limit absorption, to prolong the duration of effect, and to lessen the danger of toxicity. A concentration of 1 in 200 000 (5 micrograms/mL) is usually used; adrenaline should not be added when procedures involve digits, ears, nose, penis, or scrotum owing to the risk of ischaemic tissue necrosis. A concentration of up to 1 in 80 000 (12.5 micrograms/mL) may be used in dental preparations where the total dose given is small.
Adrenaline constricts arterioles and capillaries and causes blanching when applied locally to mucous membranes and exposed tissues. It is used as an aqueous solution in strengths up to a 1 in 1000 dilution to check capillary bleeding, epistaxis, and bleeding from superficial wounds and abrasions, but it does not stop internal haemorrhage. It is usually applied as a spray or on pledgets of cotton wool or gauze.
In ophthalmology, adrenaline solutions of 0.5%, 1%, or 2% are used as eye drops instilled once or twice daily to reduce intra-ocular pressure in open-angle glaucoma and ocular hypertension. An adrenaline borate complex (epinephryl borate) is also used.
Advanced cardiac life support.
Adrenaline has an important role in advanced cardiac life support ( <850-a4-39-b.htm> <850-a4-39-b.htm>) since, through its alpha agonist effects, it causes peripheral vasoconstriction, thus increasing myocardial and cerebral blood flow. This should improve the efficacy of cardiopulmonary resuscitation or basic life support procedures, although there is no clinical trial evidence for benefit.1 Depending on the arrhythmia that has led to cardiac arrest, treatment starts with cardiopulmonary resuscitation and defibrillation. If these measures fail to restore a conventional rhythm, the next step involves the use of adrenaline.
For adults, adrenaline is given in a dose of 1 mg, ideally intravenously into a central vein. If such venous access is not practicable adrenaline may be given through a peripheral vein followed by a flush of 20 mL or more of sodium chloride injection; however, the response is slower than with central venous injection. This intravenous dose of 1 mg may be given about every 3 to 5 minutes2-5 in further cycles of cardiopulmonary resuscitation and, if necessary, shocks. A higher dose of 5 mg or 100 micrograms/kg has been given but there is insufficient evidence of benefit and this is not recommended.2-5 In ventricular fibrillation or pulseless ventricular tachycardia, a resuscitation attempt may reasonably last for anything from 10 minutes to 1 hour with adrenaline being given every 3 to 5 minutes during this period. Where the arrest is associated with asystole it is unlikely that a response will be achieved after 15 to 20 minutes.
The initial dose of 1 mg is reported to be based on the dose that was given by intracardiac injection, so it would be expected that a higher dose would be required for intravenous use. Although myocardial and cerebral perfusion are increased more with higher doses, a meta-analysis6 of studies in adults found no evidence that this gave any survival benefit.
The intravenous dose for children is 10 micrograms/kg. Higher doses of 100 or 200 micrograms/kg have been used for the second and subsequent doses; however, as with adults, the use of the higher dose is not routinely recommended and both retrospective7 and prospective8 studies have found no improvement in outcome.
The intraosseous route is a practicable alternative to intravenous injection for adults as well as for children; doses are identical to those given intravenously. Alternatively, adrenaline can be given through the endotracheal tube that will have been inserted, but only if the intravenous or intraosseous route is unavailable. Endotracheal doses for adults should be 2 to 3 times those used intravenously; for children doses of 100 micrograms/kg have been suggested. The adrenaline solution should be diluted and administered deeply using a catheter; several rapid ventilations or inflations should follow. It is recognised that the endotracheal route is imperfect2-4 and some workers consider it to be ineffective.9
Although covering a somewhat different clinical situation some guidelines also include resuscitation of newborn infants (during the first few hours after birth).2-5 Adrenaline may be used when the heart rate remains below 60 beats/minute despite adequate ventilation and chest compression. The dose of adrenaline is 10 to 30 micrograms/kg given intravenously (generally into the umbilical vein) or by intraosseous injection. If neither of these routes are available, it may be given via the endotracheal tube; standard doses are probably ineffective and doses of up to 100 micrograms/kg may be required, although there is little evidence to support this.2,4,5
Anaphylaxis and anaphylactic shock.
Anaphylaxis is usually a type 1 hypersensitivity reaction ( <6100-a7-2-c.htm> <6100-a7-2-c.htm>) in which there is IgE-mediated activation of mast cells and basophils, usually as a result of exposure to allergens such as drugs, foods, latex, and insect venoms. A clinically identical reaction can, however, be provoked by a type II mechanism, as in blood transfusion reactions, or a type III mechanism, as in drug-induced serum sickness reactions; anaphylactoid reactions are similar, but are caused by direct histamine release rather than hypersensitivity. Symptoms of anaphylaxis and anaphylactoid reactions include erythema, pruritus, urticaria, and angioedema; respiratory obstruction may result from oedema of the larynx or epiglottis. Gastrointestinal disturbances, bronchospasm, hypotension, and coma can occur in severe reactions.
Anaphylaxis is a medical emergency and prompt treatment of laryngeal oedema, bronchospasm, and hypotension is necessary. Adrenaline causes bronchodilatation and peripheral vasoconstriction, reducing oedema and increasing blood pressure, and is the cornerstone of management.1-9 However, it may not always be effective,5 and its use is not without hazard.10 Antihistamines and corticosteroids may also have a role.
In early anaphylaxis, adrenaline is given by intramuscular injection. At this stage, vasodilatation is the main pathological change and cardiac output and blood flow to skin and muscle may be increased enabling intramuscular absorption of adrenaline to be sufficiently rapid and effective. The subcutaneous route has been used, especially by patients treating themselves, but intramuscular absorption is more rapid and is generally preferred.3,5,6 Prefilled syringes for intramuscular or subcutaneous use may be given to those known to be at high risk of developing anaphylactic shock, allowing patients to self-administer their initial emergency treatment; however, they should still seek medical assistance as additional treatment may be required. Adrenaline has been given by inhalation in milder reactions, often with an antihistamine.11 However, this should not be a substitute for adrenaline injection in patients with severe symptoms or a history of acute attacks, and the number of inhalations required may limit the use of this route in children.12 As anaphylaxis progresses the intravascular volume becomes depleted, leading to the development of shock. At this stage it is probably necessary to give adrenaline intravenously, since absorption from other routes will be compromised; however, this route is hazardous and should only be used in life-threatening situations.3,5,10 The general principles used in the management of hypovolaemia and hypotension in shock are outlined on <850-a4-43-e.htm> <850-a4-43-e.htm>.
The dose of adrenaline for intramuscular injection is usually 500 micrograms (0.5 mL of a 1 in 1000 solution); this may be repeated at 5-minute intervals, according to blood pressure and pulse, until improvement occurs. A lower dose of 300 micrograms may be used,3,5 particularly if given by auto-injector.5 Similar doses have been given subcutaneously. A more dilute solution of 1 in 10 000 is used intravenously; the dose is 500 micrograms (5 mL) given slowly at a rate of 100 micrograms/minute (1 mL/minute), stopping when a response has been obtained.
Various adrenaline dosage regimens have been suggested for children.2,5,6 In one widely used regimen, the intramuscular dose using the 1 in 1000 solution is 50 micrograms (0.05 mL) for those under 6 months, 120 micrograms (0.12 mL) for those aged 6 months to 6 years, and 250 micrograms (0.25 mL) for children aged 6 to 12 years. Doses of 150 or 300 micrograms may be given if an auto-injector is used, but may not be suitable for children weighing less than 15 kg. The intravenous dose for children, using the 1 in 10 000 solution, is 10 micrograms/kg (0.1 mL/kg).
A slow intravenous injection of an antihistamine, such as chlorphenamine 10 to 20 mg, may be given immediately after the adrenaline and repeated over the next 24 to 48 hours to prevent relapse. Although antihistamines are particularly effective in the management of angioedema, pruritus, and urticaria, they remain second-line treatment. Intravenous corticosteroids have little place in the immediate management of anaphylaxis, since their beneficial effects are delayed for several hours, but in severely ill patients early use of hydrocortisone 100 to 500 mg as the sodium succinate may help prevent deterioration after the primary treatment has been given. It has been suggested that asthmatics who have relatively recently undergone regular corticosteroid treatment should also be given hydrocortisone.5 Patients should also receive oxygen as required.
Continuing deterioration with circulatory collapse, bronchospasm, or laryngeal oedema requires further treatment including intravenous fluids, a nebulised beta2 agonist (such as salbutamol or terbutaline), intravenous aminophylline, assisted respiration (if necessary), and possibly, emergency tracheostomy.3,4
Patients receiving non-cardioselective beta blockers may be relatively refractory to the effects of adrenaline used for anaphylactic shock (see under Interactions for Sympathomimetics, <23112-s.htm> <23112-s.htm>); in such cases the use of a more selective beta2 agonist such as salbutamol by intravenous injection should be considered. Glucagon is another alternative to adrenaline in such patients.3,13 Vasopressin has also been used successfully,14 including in a patient who failed to respond to adrenaline.
Prevention of anaphylaxis is important7,8 and primarily involves avoidance of known allergens; other measures include desensitisation, particularly in patients who have reacted to bee or wasp venom.