Epinephrine

Epinephrine is a non selective adrenergic agonist and a valuable resuscitative drug because of its effects at multiple adrenergic receptor subtypes.

In the treatment of anaphylaxis, epinephrine increases myocardial contractility, accelerates heart rate, causes constriction of vascular smooth muscle, and causes relaxation of bronchial smooth muscle.

The principal pharmacologic effects of epinephrine that are beneficial in anaphylaxis are mediated via: alpha-1 receptors in vascular smooth muscle, resulting in vasoconstriction, beta-1 receptors in the heart, resulting in increased contractility, and beta-2 receptors in bronchial smooth muscle, resulting in relaxation and relief of bronchoconstriction. (One simple mnemonic for the respective locations of beta1 and beta2 receptors is “one heart, two lungs.”)

Beta-2 receptors are also found, however, in vascular smooth muscle (especially in skeletal muscle beds), were, just as in bronchial smooth muscle, they promote relaxation.

(Epinephrine dilates skeletal muscle vascular beds to maximize oxygen delivery for the “fight-or-flight” response.)

The resulting vasodilation in skeletal muscle vascular beds would, by itself, tend to decrease blood pressure, which might tend to worsen the effects of anaphylactic shock, but this effect is mitigated by the intense alpha-1 receptor stimulation, causing vasoconstriction in multiple beds.

The principal action of alpha-2 receptors is at the presynaptic nerve terminal, where receptor stimulation reduces the release of norepinephrine from the nerve terminal. Epinephrine does stimulate these receptors, but it does not really contribute to the beneficial actions of epinephrine in resuscitation.

Hypertension in pheochromocytoma results from the direct effect of high circulating levels of catecholamines, primarily noradrenaline, adrenaline, and dopamine.

Some tumors produce the catecholamine precursor L-dopa.

Pheochromocytomas also secrete numerous other peptide hormones, among which are renin, VIP, neuropeptide, Y, somatostatin, and ET-1.

These substances are responsible for many of the nonhypertensive symptoms seen in patients with pheochromocytoma, including flushing, sweating, and diarrhoea.

Ref: Pediatric Nephrology, 5e By Ellis D. Avner, William E. Harmon, Ellis D. Avner William Harmon Patrick Niaudet, 2003, Page 1167; Harrison’s Internal Medicine > Chapter 337. Pheochromocytoma

Tyrosine is the precursor for the synthesis of catecholamines namely dopamine, epinephrine and norepinephrine.

Injection therapy for bleeding peptic ulcer is performed with the use of a sclerotherapy needle to inject epinephrine.

D i.e. Epinephrine

B i.e. Epinephrine

D i.e. Insulin

A i.e. Glucocorticoids; B i.e. GH; C i.e. Epinephrine

A i.e. Epinephrine; B i.e. GH; C i.e. Glucocorticoid

Glucagon, catecholamines (epinephrine & norepinephrine), cortisol, ACTH, GH (growth hormone) are increased in stress (infection, surgery, hypoglycemia) whereas, insulin is suppressed (decreased)Q.

• In maintenance of internal homeostasis (ie avoiding stress) and reproduction processes, multiple hormones cooperate to bring about organized biochemical & physiological responses.

Stress Syndrome: CRH – ACTH – Cortisol Axis

• The primitive signal of glucose (substrate) lack is expanded to a broder signal of fright or stress and evokes a coordinated neural and endocrine response. Any stressful event eg. surgery, infection, burn triggers a hypermetabolic state in which a resting energy expenditure is increased alongwith body temperature.
• CRH-ACTH – cortisol axis is central to this integrated response to stress.

• Features of Stress Syndrome

  – Corticotropin releasing hormone (CRH) is increased in response to noxious environmental stimuli like pain, trauma,

  hypoglycemia, infection, surgery, hypovolemia. Various nervous impulses using several neuro transmitters (NTs) like norepinephrine, serotonin, acetylcholine, dopamine, and GABA reach CRH neurosecretory cells and cause release of CRH

  –                In response to CRH, both ACTH and p endorphins (secreted 13-LPH & mature p-endorphin) are released in equimolar quantities 13-endorphin produce central analgesic response.

  – Glucagon & catecholamines (epinephrine & norepinephrine) are increased, stimulating glycogenolysis (glucose

  production in liver) for immediate use by critical organs such as the brain.

  –                Cortisol production is increased in adrenal cortex which induces gluconeogenesis (glucose production from noncarbohydrate source like muscles & other body proteins)

  –                Glucogon, epinephrine, ACTH and growth hormone (GH) stimulate lipolysis and free fatty acids (FFA) & ketones are

  released into the circulation to be used as an alternative metabolic fuel.

  –                Insulin is suppressedQ that results in decrease in glucose utilization.

  –                One form of stress that is cold, specially in neonate causes increased TRH secretion due to depressed metabolism of neurons in pre- optic area by cooling which release inhibitory discharge, permitting TRH secretion.

  –                ADH (vasopressin), angiotensin & aldosterone synthesis is increased enhancing salt water retention

  –                So increased glucose production (by glycogenolysis & gluconeogenesis) and decreased utilization of glucose results in hyperglycemia. There is marked increase in release of aminoacids from tissue protein, particularly from skeletal muscle for gluconeogenesis. However, synthesis of specific proteins may increase

  –                These metabolic changes are coordinated with increased sympathetic nervous system activity causing peripheral vasoconstriction and increased blood pressure.

A i.e. Glycogenolysis

Ans. is ‘a’ i.e., Increased glucagon; ‘b’ i.e., Decreased insulin secretion

Ans. is ‘b i.e., Increase S.A. node activity [Ref: Goodman Gilman ll’^h/e p. 245; Katzung 11⁶/e p. 139] “Epinephrine speeds the heart by accelerating the slow depolarization of SA nodal cells that takes place during diastole, i.e., during phase 4 of the action potential. Consequently, the transmembrane potential of the pacemaker cells rises more rapidly to the threshold level of action potential initiation. The amplitude the action potential and the maximal rate of depolarization (phase 0) also are increased.”

Ans. is ‘a’ i.e., Adrenaline

o First adrenaline should be given im to raise the blood pressure and to dilate the bronchi.

o If the treatment is delayed and shock has developed, adrenaline should be given i.v. by slow injection.

Ans. is ‘d’ i.e., Intramuscular

o Both subcutaneous and intramuscular routes are recommended for adrenaline use in anaphylactic shock.

o However, intramuscular route of administration is superior and therefore is the route of choice for the treatment of anaphylactic shock. The lateral aspect of thigh is the site of choice.

o Subcutaneous route is second choice.

Ans. is ‘b’ i.e., Epinephrine injection

• Generalized urticaria, swelling of lips, hypotension and bronchospasm within 5 minutes of taking penicillin suggest the diagnosis of anaphylactic type of hypersensitivity.
• Epienephrine (S.C./i.m.) is DOC for anaphylactic shock.

Ans. is ‘a’ i.e., Von Girke’s disease

o Amongst the given options only Von Girke’s disease presents with hepatomegaly and hypoglycemia.

“A diagnosis of type I glycogen storage disease (Von Girke’s disease) should be suspected whenever there is hepatomegaly with hypoglycemia that is unresponsive to glucagon or epinephrine”.

B i.e. Epinephrine

B i.e. Epinephrine, C i.e. Bretylium, A i.e. Isoproterenol

Bupivacaine (R, +) isomer avidly blocks cardiac sodium channels & dissociates very slowly; its prolonged & high degree of protein binding makes resuscitation difficult & prolonged. At higher doses calcium & potassium channels are also blocked. Bupivacaine is more cardiotoxic than levobupivacaine, ropivacaine and lidocaine, particularly in presence of acute respiratory acidosis, hypoxemia, hypercapnia in pregnancy (>>) and young children.

– Amiodarone and possibly bretylium should be considered as preferred alternative to lidocaine in the treatment of LA induced ventricular tachyarrhythmias. Vasopressors may include epinephrine, norepinephrine and vasopressinQ. IsoproterenolQ may effectively reverse some of electrophysiological abnormalities characteristic of bupivacaine toxicity.

–                                 If LA intoxication produces cardiac arrest, the ACLS (advanced cardiac life support) guidelines are reasonable; however, I suggest that amiodarone & vasopressin be preferredQ/substituted for lidocaine & epinephrine (ACLS prefers epinephrine) – Morgan/273. With unresponsive bupivacaine toxicity, intravenous lipid infusion (remarkable ability to effect resuscitation from overdose even after 10 min of unsuccessful conventional resuscitation) or cardiopulmonary bypass may be considered.

Calcium channel blockers are not recommended as these exaggerate the cardiodepressant effectsQ.

C i.e. Aphakic glaucoma

• Epinephrine (sympathomimetic drugs) should be avoided in aphakics Q due to possibility of cystoid macular oedema and in narrow angle glaucoma Q because mydriasis may precipitate the attack.
• In inflammatory glaucoma (uveitis glaucoma), prostaglandin analogue & pilocarpine are contraindicatedQ

Ans. Reduces aqueous production and increases outflow facility

Ans. Pigmented pupillary cyst

Ans. B: Epinephrine

Anaphylaxis

• It is defined as “a serious allergic reaction that is rapid in onset and may cause death”.
• It can result in a number of symptoms including throat swelling, an itchy rash, and low blood pressure.
• On a pathophysiologic level it is an acute multi-system type I hypersensitivity reaction.
• “True” anaphylaxis is caused by degranulation of mast cells or basophils mediated by immunoglobulin E (IgE), and pseudo-anaphylaxis occurs without IgE mediation
• The most common areas affected include: skin (80% to 90%), respiratory (70%), gastrointestinal (30% to 45%), heart and vasculature (10% to 45%), and central nervous system (10% to 15%)
• Skin involvement may include generalized hives, itchiness, flushing, and swelling of the lips, tongue, or throat.
• Respiratory symptoms may include shortness of breath, wheezes or stridor, and low oxygen.
• Gastrointestinal symptoms may include crampy abdominal pain, diarrhea, and vomiting.
• Anaphylaxis can occur in response to any allergen.
• Common triggers include insect bites or stings, foods, medication, and latex rubber.
• Foods are the most common trigger in children and young adults while medications and insect bites and stings are more common in older adults.
• Biphasic anaphylaxis is the recurrence of symptoms within 1-72 hours with no further exposure to the allergen.
• Anaphylactic shock is anaphylaxis associated with systemic vasodilation that results in low blood pressure.
• It is also associated with severe bronchoconstriction to the point where the individual is unable to breathe.
• Pseudoanaphylaxis has a similar presentation and treatment to that of anaphylaxis, however, it does not involve an allergic reaction but is due to direct mast cell degranulation.
• This can result from morphine, radiocontrast, aspirin and muscle relaxants.
• Epinephrine (adrenaline) is the primary treatment for anaphylaxis with no absolute contraindication to its use.
• It is recommended that it be given intramuscularly into the mid anterolaterial thigh as soon as the diagnosis is suspected.
• Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.

Ans. is ‘a’ i.e., Adrenaline

Ans. is ‘b’ i.e., 0-2 ml

Epinephrine

• The IV dose of 1: 10,000 concentration is 0.1m1/Kg. Thus it is about 0.5ml for term baby and 0^.2 ml for pre term baby.
• Endotracheal tube dosing is 1m1/ Kg. thus it is about 3m1 for term baby and 1 ml for preterm.

Ans. is ‘d’ i.e., Adrenal medulla 

Ans. is ‘b’ i.e., Epinephrine

• Among the given options, only epinephrine has significant action on a-receptor, thus causes vasoconstriction.

Svmpathomimetic drugs

• Non selective
• Adrenaline → a, + a, + 13, + [3,
• Noradrenaline→ a, + a, + [3, + Slight 13, no. 132
• Isoprenaline→ R + [3₂+ 13₃ but no a action
• Mephentramine→ a and 13

Selective

• a_l agonists →  Phenylephrine, methoxamine, naphazoline, oxymetazoline, xylometazoline.
• a, agonists→ Clonidine, methyldopa, brimonidine, apraclonidine, guanfacine, guanabenz
• 13, agonists→ Prenalternol, dobutamine
• [3, agonsits → Salbutamol, terbutaline, salmeterol, orciprenaline, ritodrine, isotharine, bitolterol, pirbuterol, tenoterol, formoterol.

Ans. is ‘c’ i.e., Metyrosine