ANAPHYLAXIS
Certain allergens, especially drugs, insect venoms, and foods, may
induce an IgE antibody response, causing a generalized release of mediators
from mast cells and resulting in systemic anaphylaxis. This is characterized by
(1) hypotension or shock from widespread vasodilation, (2) bronchospasm, (3)
gastrointestinal and uterine muscle contraction, and (4) urticaria or
angioedema. The condition is potentially fatal if not treated immediately and
appropriately. Isolated urticaria and angioedema are cutaneous forms of
anaphylaxis, are much more common, and have a better prognosis.
Penicillin Allergy.
Hypersensitivity reactions are the most common adverse effects noted
with the penicillins, and these agents are probably the most common cause of
drug allergy. The allergic reactions include anahylaxis, serum sickness, skin
rashes, fever, interstitial nephritis, eosinophilia, hemolytic anemia, and
vasculitis. The incidence of penicillin allergy is estimated to be 1 – 5% among
adults in the USA.
Life-threatening anaphylactic reactions are very rare (0.05%).
Treatment of anaphylactic reactions.
Anaphylactic shock and related immediate (type I) IgE-mediated
reactions affect both the respiratory and the cardiovascular systems.
The syndrome of bronchospasm, mucous membrane congestion,
angioedema, and severe hypotension usually responds rapidly to the parenteral
administration of epinephrine (adrenaline), 0.3 – 0.5 mg ( 0.3 – 0.5 ml of 1:
1000 epinephrine solution) every 10 -20 minutes. Intramuscular injection into
the lateral thigh may be the preferred route of administration, since skin
blood flow (and hence systemic drug absorption from subcutaneous injection) is
unpredictable in hypotensive patients. The administration of epinephrine is
usually followed by corticosteroids (250 mg hydrocortisone or 50 mg of
methylprednisolone intravenously every 6 hours for two or four doses), if
needed.
In some patients with impaired cardiovascular function, intravenous
injection of epinephrine may be required. Extensive experimental and clinical experience
with the drug in anaphylaxis supports epinephrine as the drug of choice,
presumably because epinephrine activates α, β1, and β2
receptors, all of which may be important in reversing the pathophysiologic
processes underlying anaphylaxis. Glucocorticoids and antihistamines (both H1-
and H2-receptor antagonists) may be useful as secondary therapy in
anaphylaxis; however, epinephrine is the initial treatment.
Persistent hypotension should be treated with intravenous fluids
(saline or colloid), epinephrine (1 ml of 1:1000 dilution in 500 ml of
intravenous fluid at a rate of 0.5 – 5 mcg/min), and antihistamines (25-50 mg
of hydroxyzine or diphenhydramine intramuscularly or orally every 6-8 hours as
needed).
Epinephrine (adrenaline) is a very potent vasoconstrictor and
cardiac stimulant. The rise in systolic blood pressure that occurs after the
administration of epinephrine is caused by its positive inotropic and
chronotropic action on the heart
(predominantly β1 receptors) and the vasoconstriction induced in
many vascular beds (α receptors). Epinephrine also activates β2
receptors in some vessels (eg. skeletal muscle blood vessels) leading to
vasodilation. Consequently, total peripheral resistance may actually fall,
explaining the fall in diastolic pressure that is sometimes seen with
epinephrine injection.
Epinephrine opposes histamine; it relaxes bronchiolar smooth muscle
and contracts vascular muscle, relieving both bronchospasm and hypotension.
The antihistamines competitively inhibit histamine, which would
otherwise produce bronchoconstriction and increased capillary permeability in
the end organ.
Glucocorticoids are immunosuppressive; it blocks proliferation of
the IgE producing clones and inhibits IL-4 production by T helper cells in the
IgE response. Glucocorticoids may also act to reduce tissue injury and edema in
the inflamed tissue, as well as facilitating the action of catecholamines in
cells that may have become refractory to epinephrine.
DOPAMINE
Dopamine, the immediate metabolic precursor of norepinephrine ,
activates D1 receptors in several vascular beds, which lead to
vasodilation. The effect of dopamine on renal blood flow can be of clinical
value. The activation of presynaptic D2 receptors, which suppress
norepinephrine release, contributes to these effects to an unknown extent. In
addition, dopamine activates β1- receptors in the heart. At low
dose, peripheral resistance may decrease. At higher rates of infusion, dopamine
activates vascular α1 receptors, leading to vasoconstriction,
including in the renal vascular bed. Consequently, high rates of infusion of
dopamine may mimic the actions of epinephrine.
Dopamine is used in the treatment of shock accompanied by poor
perfusion, low cardiac output, and impending renal failure associated with such
conditions as myocardial infarction (cardiogenic shock), severe trauma,
septicaemia, and after cardiac surgery. Because of its tendency to decrease
peripheral resistance in low to medium doses, and also to reduce intravascular
volume, the blood volume should be restored with plasma expanders when
necessary before dopamine is used.
Mode of action.
In low dosages (1-5 mcg/kg/min) dopamine is active on dopamine
receptors in renal arterioles and causes renal vasodilation, which results in
increased renal flow and diuresis.
In higher dosages (5-20 mcg/kg/min) dopamine acts on cardiac β1-adrenoceptors
and produces a positive inotropic effect.
Very large dosages of dopamine (above 20 mcg/kg/min) act on
α-adrenoceptors, causing tachycardia, cardiac arrhythmia, and vasoconstriction,
with deleterious effects, such as hypertension, angina, and even renal
vasoconstriction.
Dosages.
The mode of administration of dopamine is important. It is usually
given intravenously in a final concentration of 1600 microgram/ml (i.e. 800 mg
of dopamine in 500 ml of physiological saline or 5 % dextrose).
Infusion is usually started at 2 mcg/kg/min and the dosage should be
increased in increments of 5 micrograms/kg/min according to the patient’s response, monitored by measuring urine
output, blood pressure, vascular perfusion, heart rate, and central venous
pressure.
The maximum dose should usually be 20 mcg/kg/min. Higher dosages
have been used, but careful monitoring for adverse effects is necessary.
Important adverse effects.
In high dosages sinus tachycardia, extra beats and other
arrhythmias, and vasoconstriction (with the risks of angina, hypertension, and
renal impairment) are almost inevitable. Other common adverse effects include
nausea, vomiting, and dyspnoea. If
accidental overdosage occurs, the α-adrenergic effects, such as hypertension,
can be quickly controlled by discontinuing the infusion and administering the
alfa-adrenoceptor antagonist phentolamine intravenously.
Dopamine should not be used in patients taking MAO inhibitors, since
they inhibit its metabolism. It should not be infused in alkaline solutions,
which inactivate it.
DOBUTAMINE
Dobutamine is a synthetic catecholamine . The pharmacological
effects of dobutamine are due to direct interactions with α and β receptors.
Although dobutamine originally was thought to be relatively selective β1 receptor agonist, it is now clear that its
pharmacological effects are complex.
Dobutamine possesses a center of asymmetry; both enantiometric forms
are present in the racemic mixture used clinically. The levo-isomer of
dobutamine is a potent agonist at α1-receptors
and is capable of causing marked pressure responses. In contrast, dextro-dobutamine is a potent α1-receptor
antagonist, which can block the effects of levo-dobutamine. The effects of these two isomers are mediated
via β-receptors. The dextro-isomer is a
more potent β-receptor agonist than the levo-isomer (approximately 10 fold).
Both isomers appear to be full agonists.
Therapeutic Uses.
Dobutamine is indicated for the short-term treatment of cardiac
decompensation that may occur after cardiac surgery or in patients with
congestive heart failure or acute myocardial infarction.
Dobutamine increases cardiac output and stroke volume in such
patients, usually without a marked increase in heart rate.
Dobutamine has a half-life of about 2 minutes. The major metabolites
are conjugates of dobutamine and 3-O-methyldobutamine. The onset of effect is
rapid. Consequently , a loading dose is not required, and the steady-state
concentration is achieved within 10 minutes of initiation of the infusion. The
rate of infusion required to increase cardiac output is between 2.5 and 10
ug/kg/min. The rate and duration of infusion are determined by the clinical and
the hemodynamic responses of the patients.
Adverse effects.
In some patients, blood pressure and heart rate increase
significantly during dobutamine administration; this may require reduction of
the rate of infusion. Patients with history of hypertension may exhibit an
exaggerated pressor response more frequently. Patients with atrial
fibrillation are at risk of marked increases in ventricular response
rates; digoxin or other measures may be required to prevent this from
occurring. Some patients may develop ventricular ectopic activity.
LIDOCAINE (Antiarrhythmic agent
subgroup 1B)
Lidocaine has a low incidence of toxicity and a high degree of
effectiveness in arrhythmias associated with acute myocardial infarction.
Extensive first-pass metabolism to a toxic metabolite prevents oral
administration of lidocaine. It is usually given intravenously, initially as a
loading dose by bolus injection followed by an infusion. Lidocaine is
metabolized in the liver to compounds with little antiarrhythmic action, but
they can cause seizures.
Lidocaine is the agent of choice for termination of ventricular
tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute myocardial
infarction. Sustained ventricular tachycardia should be treated with a 1mg/kg
bolus of lidocaine if the patient is stable or by electrical cardioversion if
not.
If the arrhythmia can not be suppressed with lidocaine, procainamide
(100 mg boluses over 1-2 minutes every 5 minutes to a cumulative dose of 750-1000
mg) or intravenous amiodarone (150 mg over 10 minutes, which may be repeated as
needed, followed by 360 mg over 6 hours and then 540 mg over 18 hours) should be initiated,
followed by an infusion of 20-80 mg/kg/min.
However, routine prophylactic use of lidocaine in this setting may
actually increase total mortality, possibly by increasing the incidence of
asystole, and is not the standard of care. Most physicians administer
intravenous lidocaine only to patients with arrhythmias.
Ventricular fibrillation is treated by electrical cardioversion.
Unresponsive ventricular fibrillation should be treated with additional
amiodarone and repeat cardioversion while cardiopulmonary resuscitation (CPR)
is administered.
Unwanted effects of lidocaine include nausea and vomiting, CNS
toxicity (eg. muscle twitching, convulsion, dizziness, drowsiness), negative
inotropic effect (myocardial depression), bradycardia, and proarrhythmic
effects.
REFERENCES
1.
Aronson & Richards (2005). Oxford Handbook of Practical Drug Therapy, Oxford University
Press, UK.
2.
Grahame-Smith & Aronson
(1994). Oxford Textbook of Clinical Pharmacology
and Drug Therapy, 2nd Edition, Oxford
University Press, UK.
3.
Goodman & Gilman’s The
Pharmacological Basis of Therapeutics (2006), 11th Edition,
McGraw-Hill Companies, USA.
4.
Katzung, B.G. (2007). Basic And
Clinical Pharmacology, 10th Edition, The McGraw-Hill Companies, USA.
5.
McPhee & Papadakis :
Current Medical Diagnosis & Treatment (2009), 48th Edition, The
McGraw-Hill Companies, USA.
