DRUG PROFILE Adrenaline

Phenytoin is an oral and injectable anti-seizure medication first synthesized in 1908. Phenytoin was originally approved by the FDA in 1939.

Active Ingredient Drug Category WHO Essential Drug List

National Essential Drug List

Adrenaline Hydrochloride Prescription 3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS 12.2 Antiarrhythmic medicines 25. MEDICINES ACTING ON THE RESPIRATORY TRACT 25.1 Antiasthmatic and medicines for chronic obstructive pulmonary Disease

Adrenaline; Mobahil Ahmad

Product Description
Serial No. 1. Brand Manufacturer Name Adrenaline PDH Inj. Pharmaceuticals Pvt. Ltd. Adrenaline Elite Inj. Pharmaceuticals MB-CAIN MBL Pharma Xylocaine Barret Hodgson with Pakistan Pvt. Adrenaline Ltd. Dosage Form Injection Strength 1ml Pack Size 1ml100s 1ml100s 50s 50s 50s Price/Unit PKR 169.39

2. 3. 4.

Injection Injection Ampule

1ml 10ml 10ml plus Adrenaline 1:200000 sterile clear aqueoussolution 10 ml

PKR 144.62 PKR 600 PKR 650 PKR 810

How to store this drug:

Store under nitrogen. Epinephrine injection should be stored at room temperature (approximately 25 C). Preserve in tight, light-resistant containers. In some commercially available injections, the air has been replaced with nitrogen to avoid oxidation. Withdrawal of doses from multiple-dose vials introduces air into the vials, subjecting the remaining epinephrine to oxidation. Oxidation of the drug imparts first a pink, then a brown color; epinephrine preparations must not be used if they have a pinkish or darker than slightly yellow color or contain a precipitate.

Adrenaline; Mobahil Ahmad

Chemistry of Drug
Chemical Class Structure Catecholmine (Biogenic Amines)
(R)-1-(3,4-Dihydroxyphenyl)-2-methylaminoethanol. 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol (IUPAC)

Chemical Nature

CAS Melting Point Stability:

pKa Spectral Properties

51-43-4. 211.5 C Stable. Incompatible with acids, acid chlorides, anhydrides & oxidizing agents. Light sensitive. 8.28 Specific optical rotation = -53 deg at 20 deg C/D (aqueous HCl) Absorption spectrum in 0.1M HCl: lambda max 221 nm (epsilon about 6100); lambda max 280 nm (epsilon about 2700) IR: 1566 (Coblentz Society Spectral Collection) UV: 1512 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) A white to practically white, gradually darkening on exposure to light and air. USP 31 (Epinephrine). Odourless microcrystalline powder or granules. USP 31 (Epinephrine). With acids, it forms salts that are readily soluble in water, and the base may be recovered by the addition of ammonia water or alkali carbonates. Very slightly soluble in water and in alcohol; insoluble in chloroform, in ether, and in fixed and volatile oils. Solutions are alkaline to litmus. USP 31 (Epinephrine).

Physical Properties

Colour

State/Form Description

Adrenaline; Mobahil Ahmad

Pharmacokinetics
Absorption
Oral : Nil Systemic absorption can occur after topical application for example of eye drops. Usually this vasodilator effect of the drug on circulation predominates so that the modest rise in systolic pressure which follows slow injection or absorption is mainly the result of direct cardiac stimulation and increase in cardiac output.

Distribution
Bioavailability Protein Binding (%) Placental Barrier Blood Brain Barrier Secreted in Milk Volume of Distribution

Crosses the placenta

Excretion in breast milk unknown

Bronchodilation & SubQ: 5-10 minutes Inhalation: 1 minute

Time of onset of action Elimination

Half life (elimination) Site of Metabolism

2 minutes Epinephrine is rapidly inactivated in the body and is degraded by enzymes in the liver and other tissues. Main metabolic enzymes include MAO and COMT

Active Metabolite (if any) Renal/Kidney Route of Excretion a) Poisoning and Toxicology handbook; fourth edition by Jerrold B. Leikin, MD & Frank P. Paloucek, PharmD b) Martindale; The Complete Drug Reference, Thirty-sixth edition

Adrenaline; Mobahil Ahmad

Clinical Pharmacology
Pharmacological Class Therapeutic Class
Sympathomimetics Vasoconstrictor Agents Mydriatics Bronchodilator Agents Adrenergic -Agonists Adrenergic -Agonists Adrenergic Agonists Stimulates alpha-adrenergic, b1- and b2-adrenergic receptors; small doses can causes vasodilation via b2 vascular receptors; decreases production of aqueous humor and increases aqueous outflow; dilates the pupil by contracting the dilator muscle.

Mechanism of Action

Spectrum (in case of antibiotics) Contraindications

NA

Epinephrine should not be used in cardiogenic shock because it increases myocardial oxygen demand, nor should it be used in hemorrhagic or traumatic shock. Epinephrine is contraindicated in patients with shock (other than anaphylactic shock), organic heart disease, or cardiac dilation, as well as most patients with arrhythmias, organic brain damage, or cerebral arteriosclerosis. Epinephrine injection is contraindicated in patients with angle-closure glaucoma. The drug is contraindicated for use during general anesthesia with chloroform, trichloroethylene, or cyclopropane, and should be used cautiously, if at all, with other halogenated hydrocarbon anesthetics such as halothane. In conjunction with local anesthetics, epinephrine is contraindicated for use in fingers, toes, ears, nose, or genitalia. Epinephrine is contraindicated for parenteral use during the second stage of labor; parenteral administration of the drug to maintain blood pressure during spinal anesthesia for delivery can cause acceleration of fetal heart rate and should not be used in obstetric patients when maternal systolic/diastolic blood pressure exceeds 130/80 mm Hg. Epinephrine should be administered cautiously by oral inhalation to pregnant patients. Epinephrine should be used during pregnancy only if the potential benefits justify the possible risks to the fetus. There is some evidence that epidural administration of lidocaine with epinephrine during labor is safe. Repeated injections of epinephrine can cause necrosis as a result of vascular constriction at the injection site. Tissue necrosis may also occur in the extremities, kidneys,

Adrenaline; Mobahil Ahmad

and liver. Fatal gas gangrene has occurred in patients receiving IM injection of epinephrine oil suspension (no longer available) in the buttocks. It has been postulated that epinephrine-induced vasoconstriction reduces the oxygen tension of tissues, enabling anaerobic Clostridium welchii which may be present in the patient's feces and on the buttocks to multiply. IM injection of the drug into the buttocks should be avoided. If gas gangrene is suspected after epinephrine administration, treatment should be instituted immediately. Epinephrine ophthalmic preparations generally should not be used in conjunction with the wearing of soft contact lenses, since the drug may cause adrenochrome staining of the lenses.

Precautions

Use with caution in elderly patients, patients with diabetes mellitus, cardiovascular diseases (angina, tachycardia, myocardial infarction), thyroid disease, or cerebral arteriosclerosis, Parkinsons; some products contain sulfites as preservatives. Rapid I.V. infusion may cause death from cerebrovascular hemorrhage or cardiac arrhythmias. Oral inhalation of epinephrine is not the preferred route of administration. Avoid topical application where reduced perfusion could lead to ischemic tissue damage (eg, penis, ears, digits).
Contact lenses. Adrenochrome staining of soft-contact lenses of patients using adrenaline eye drops has been reported.1 Melanin deposits may also become locked into the lens; such deposits may be broken down by hydrogen peroxide. The prodrug, dipivefrinehydrochloride has been used without staining soft lenses Infection. An open study1 comparing adrenaline with dopamine for cardiovascular support in 23 patients critically ill with severe sepsis or malaria suggested that use of adrenaline was limited by the development of lactic acidosis. However, it has been pointed out2 that 20 of the patients had responded to fluids, a situation in which the use of inotropic or vasopressor support was considered questionable, and that adrenaline has been widely used in the treatment of septic shock. A further controlled study3 found that although adrenaline led to higher lactate concentrations than noradrenaline with dobutamine, the effect was transient. Nevertheless, it has been recommended4 that adrenaline should only be used in septic shock if other treatments are ineffective.

Adrenaline; Mobahil Ahmad

Clinical Monitoring Parameters

FDA Pregnancy Class

Pulmonary function Heart rate Blood pressure Site of infusion for blanching Extravasation Pregnancy Risk Factor C

Adjustment of Dosage (if required) in Renal/Hepatic Impairment

Kidney Injury:
Only a small proportion of EPI is excreted unchanged in urine. The Pharmacokinetics of EPI in patients with renal insufficiency has not been studied. Epinephrine does not require specific dose changes for renal insufficiency.

Liver Dysfunction:
Epinephrine is metabolized by COMT and MAO to inactive metabolites. Dose adjustments are not necessary for hepatic insufficiency.

Dosage Schedule
Indication Route of Administr ation I.V. Recommended Dosage Child Adult
Neonates: 0.01-0.03 mg/kg (0.1-0.3 mL/kg of 1:10,000 solution) every 3-5 minutes as needed. Although I.V. route is preferred, may consider administration of doses up to 0.1 mg/kg through the endotracheal tube until I.V. access established; dilute intratracheal doses to 1-2 mL with normal saline.

Duration of therapy (if any)

Cardiac arrest

Adrenaline; Mobahil Ahmad

Asystole/pulse less arrest, bradycardia, VT/VF (after failed defibrillations)

I.V., I.O.

Infants and Children: 0.01 mg/kg (0.1 mL/kg of 1:10,000 solution) every 3-5 minutes as needed (maximum: 1 mg)

1 mg every 3-5 minutes; if this approach fails, higher doses of epinephrine (up to 0.2 mg/kg) may be indicated for treatment of specific problems (eg, betablocker or calcium channel blocker overdose)

Continuous I.V. infusion:

Intratracheal

Infants and Children: 0.1-1 mcg/kg/; dosesB0.3 mcg/kg/minute generally produce b-adrenergic effects and higher doses generally produce a-adrenergic vasoconstriction; titrate dosage to desired effect Infants and Children: 0.1 mg/kg (0.1 mL/kg of 1:1000 solution) every 35 minutes (maximum: 10 mg)

Administer 2-2.5 mg for VF or pulseless VT if I.V./I.O. access is delayed or cannot be established; dilute in 5-10 mL NS or distilled water. Note: Absorption is greater with distilled water, but causes more adverse effects on PaO2.

Severe allergic reactions to insect stings, food, etc

I.M., SubQ.

<30 kg: 0.15 mg

0.3-0.5 mg (1:1000) every 15-20 minutes if condition requires (I.M route is preferred)
0.1 mg (1:10,000) over 5 minutes. May infuse at 1-4 mcg/minute to prevent the need to repeat injections frequently. 2-10 mcg/minute; titrate to desired effect

I.V.

Bradycardia (symptomatic) or hypotension

I.V. infusion:

Adrenaline; Mobahil Ahmad

(not responsive to atropine or pacing): Bronchodilato r:

0.3-0.5 mg (1:1000) every 20 minutes for 3 doses Nebulization: 1-3 inhalations up to every 3 hours using solution prepared with 10 drops of the 1:100 product Decongestant: Intranasal: Apply 1:1000 locally as drops or spray or with sterile swab British National Formulary 61 & BNF for Children 2011-2012

Side Effects
Cardiovascular: Pallor Tachycardia Hypertension Increased myocardial oxygen consumption Cardiac arrhythmias Sudden death Chest pain Superior mesenteric artery thrombosis Shock Ventricular arrhythmias Cardiomyopathy Cardiomegaly Angina Palpitations Sinus tachycardia Tachycardia (supraventricular) Tachycardia (ventricular, bidirectional) Vasoconstriction Pounding heartbeat Anxiety Headache Sympathetic storm Nervousness Restlessness Exfoliative dermatitis Alopecia

Central nervous system:

Dermatologic:

Adrenaline; Mobahil Ahmad

Urticarial Exanthema Endocrine & metabolic: Lactic acidosis Hyperglycemia Hypophosphatemia Hyperkalemia Hypokalemia Gastrointestinal: Nausea Intestinal ischemia Xerostomia Genitourinary: Acute urinary retention in patients with bladder outflow Obstruction Local: Tissue ischemia and necrosis with extravasation Neuromuscular & skeletal: Weakness Ocular: Precipitation of or exacerbation of narrow-angle glaucoma Vision color changes (green tinge) Renal: Decreased renal and splanchnic blood flow Miscellaneous: Allergic reactions Fixed drug eruption Poisoning and Toxicology handbook; fourth edition by Jerrold B. Leikin, MD & Frank P. Paloucek, PharmD

Administration Guidelines
For Oral Use: NA For Topical Use: NA For I/V Route: IV bolus, Rate of administration, Solvent for reconstitution (For dry powder for injection) Volume to be added / Concentration Temperature and Storage time after Reconstitution Compatible IV fluids Administer at an initial rate of 1 mcg/minute and increase to desired effects; at 20 mcg/minute pure alpha effects occur. D5W Normal Saline Dilute 1 mg in 250 mL of D5W or NS / 4 mcg/mL Store at 20C to 25C (68F 77F) The addition of phenytoin solution to IV infusion in not recommended because of lack of solubility and resultant precipitation. Do not use D5W as a diluent; D5W is incompatible with epinephrine. Ionosol PSL (Darrows) Ionosol T with dextrose 5% Sodium bicarbonate 5% 1 mcg/minute: 15 mL/hour

Pharmaceutical Incompatibilities

Infusion Rate

Adrenaline; Mobahil Ahmad

2 mcg/minute: 30 mL/hour 3 mcg/minute: 45 mL/hour

Counseling:
Do not use solutions that are pinkish or darker than slightly yellow or if they contain a precipitate. For asthma, importance of discontinuing oral inhalation therapy and contacting a clinician if symptoms are not relieved within 20 minutes or they become worse. Importance of not injecting the dose via the auto-injector into the thumb, finger, or hand since loss of blood flow may occur in these areas. Importance of informing clinicians of underlying heart disease, hypertension, thyroid disease, diabetes mellitus, or prostatic enlargement that causes difficulty urinating. Poisoning and Toxicology handbook; fourth edition by Jerrold B. Leikin, MD & Frank P. Paloucek, PharmD

Drug-Drug Interactions
Interacting drug Anesthetics, general (cyclopropane, halogenated hydrocarbons) Severity Mechanism
Increased cardiosensitivity to epinephrinea

Outcome
Use with caution, if at all; increased risk of ventricular arrhythmias such as VPCs, VT, or VF; contraindicated with chloroform, trichloroethylene, or cyclopropanea May not be absorbed rapidly enough with topical hemostatic use to present a problem in short procedures a Propylactic lidocaine or procainamide may provide some protection.

Management
IV propranolol may reverse arrhythmias.

Phenothiazine s

Reversal of epinephrine's vasopressor effect

Do not use to treat phenothiazineinduced hypotension

Drug Interaction Facts by David S. Tatro

Adrenaline; Mobahil Ahmad

Drug-Food Interactions
Food
Caffeine

Nature of Interaction

Epinephrine can increase blood pressure and heart rate. Caffeine, especially in large amounts, can also increase heart rate. When given with phenylpropanolamine, a drug with effects similar to epinephrine, caffeine has been shown to produce an additive increase in blood pressure. Caffeine is found in coffee, tea, soft drinks, chocolate, guaran (Paullinia cupana),nonprescription drugs, and supplements containing caffeine or guaran. While no interactions have been reported between epinephrine and caffeine, people using epinephrine can minimize the potential for interactions by limiting or avoiding caffeine. Vitamins and Minerals Intravenous administration of epinephrine to human volunteers reduced plasma concentrations of vitamin C. Epinephrine and other stress hormones may reduce intracellular concentrations of potassium and magnesium. Although there are no clinical studies in humans, it seems reasonable that individuals using epinephrine should consume a diet high in vitamin C, potassium, and magnesium, or should consider supplementing with these nutrients. Reference: Stockleys Herbal Medicines Interactions, Pharmaceutical Press 2009

Drug-Lab Interactions
Epinephrine causes ECG changes including a decrease in T-wave amplitude in all leads in normal persons.

Adrenaline; Mobahil Ahmad

Toxicology
The minimum lethal human dose by subcutaneous injection is estimated as 4 mg. Cardiac arrhythmias Signs & Symptoms of toxicity Hyperglycemia Hypertension (which may result in subarachnoid hemorrhage and hemiplegia) Metabolic acidosis Pulmonary edema Renal failure Tachycardia (ventricular, bidirectional) Unusually large pupils Adrenaline has a short duration of activity due to inactivation Management/Treatment in the body and treatment of severe toxic reactions in hypersensitive patients or after overdose is primarily supportive. Phentolamine injection has been successfully used to reverse the vasoconstriction, and there has also been a report of the use of iloprost infusion followed by a stellate ganglion block. a) Poisoning and Toxicology handbook; fourth edition by Jerrold B. Leikin, MD & Frank P. Paloucek, PharmD b) Martindale; The Complete Drug Reference, Thirty-sixth edition

Toxic Dose

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Adrenaline; Mobahil Ahmad