The Pharmacology of Drugs Used in Medical Emergencies

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

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3.      Goodman & Gilman’s The Pharmacological Basis of Therapeutics (2006), 11^th Edition, McGraw-Hill Companies, USA.

4.      Katzung, B.G. (2007). Basic And Clinical Pharmacology, 10^th Edition, The McGraw-Hill Companies, USA.

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