Antipyretic, analgesic Paracetamol Aspirin Ibuprofen

1. Acetaminophen (Paracetamol)

Other brands - Anacin-3, Liquiprin, Panadol, Paracetamol, Tempra, Tylenol,

Acetaminophen is a widely used drug found in many over-the-counter and prescription analgesics and cold remedies.

When it is combined with another drug such as diphenhydramine, codeine, or propoxyphene, the more dramatic acute symptoms caused by the other drug may mask the mild and nonspecific symptoms of early acetaminophen toxicity, resulting in a missed diagnosis or delayed antidotal treatment.

Mechanism of toxicity A) Hepatic injuryOne of the products of normal metabolism of acetaminophen

by cytochrome P-450 mixed-function oxidase enzymes is highly toxic; normally this reactive metabolite (NAPQI) is detoxified rapidly by glutathione in liver cells. However, in an overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing liver injury.

B) Renal damage Renal damage may occur by the same mechanism, owing to

renal P-450 metabolism.C) PregnancyOverdose during pregnancy has been associated with fetal

death and spontaneous abortion.

Pharmacokinetics Absorption: Rapidly absorbed, with peak levels usually

reached within 30–120 minutes (Note: Absorption may be delayed

after ingestion of sustained-release products or with co-ingestion of opioids or anticholinergics).

Distribution: Volume of distribution (Vd) = 0.8–1 L/kg. Elimination: is mainly by liver conjugation (90%) to nontoxic

glucuronides or sulfates; cytochrome P-450 mixed-function oxidase (CYP 2E1, 1A2) accounts for only about 3–8% but produces a toxic intermediate.

The elimination half-life is 1–3 hours after a therapeutic dose and may be greater than 12 hours after an overdose.

Toxic dose A. Acute ingestion of more than 200 mg/kg in children or 6–7 g

in adults is potentially hepatotoxic.1. Children younger than 10–12 years of age appear to be less

susceptible to hepatotoxicity because of the smaller contribution of cytochrome P-450 to acetaminophen metabolism.

2. In contrast, the margin of safety is lower in patients with induced cytochrome P-450 microsomal enzymes, because more of the toxic metabolite may be produced. High-risk patients include alcoholics and patients taking inducers of CYP 2E1 such as isoniazid. Fasting and malnutrition also increase the risk of hepatotoxicity, presumably by lowering cellular glutathione stores.

B. Chronic toxicity has been reported after daily consumption of supratherapeutic doses by alcoholic patients and persons taking isoniazid. Children have developed toxicity after receiving as little as 60–150 mg/kg/day for 2–8 days.

Clinical presentation Clinical manifestations depend on the time after ingestion.

A. Early after acute acetaminophen overdose, there are usually no symptoms other than anorexia, nausea, or vomiting.

Rarely, a massive overdose may cause altered mental status and metabolic acidosis. Transient prolongation of the prothrombin time (PT/INR) in the absence of hepatitis has been noted in the first

24 hours; some, but not all, of these patients go on to develop liver injury.

B. After 24–48 hours, when transaminase levels [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] begin to rise, hepatic necrosis becomes evident. If acute fulminant hepatic failure occurs, death may ensue.

Encephalopathy, metabolic acidosis, and a continuing rise in PT/INR indicate a poor prognosis.

Acute renal failure occasionally occurs, with or without concomitant liver failure.

Diagnosis Prompt diagnosis is possible only if the ingestion is suspected

and a serum acetaminophen level is obtained. However, patients may fail to provide the history of

acetaminophen ingestion, because they are unable (eg, comatose from another ingestion), unwilling, or unaware of its importance.

Therefore, many clinicians routinely order acetaminophen levels in all overdose patients regardless of the history of substances ingested.

A. Specific levels1. After an acute overdose, obtain a 4-hour postingestion

acetaminophen level and use the nomogram to predict the likelihood of toxicity. Do not attempt to interpret a level drawn before 4 hours unless it is "nondetectable." Obtain a second level at 8 hours if the 4-hour value is borderline or if delayed absorption is anticipated.

2. The nomogram should not be used to assess chronic or repeated ingestions.

3. Falsely elevated acetaminophen levels may occur in the presence of high levels of salicylate and other interferents by various methods. This problem is rare with currently used analysis methods.

B. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, liver transaminases, and PT/INR.

Treatment A. Emergency and supportive measures1. Spontaneous vomiting may delay the oral administration of

antidote or charcoal and should be treated with metoclopramide or a 5-HT3 receptor antagonist such as ondansetron (Ondansetron).

2. Provide general supportive care for hepatic or renal failure if it occurs. Emergency liver transplant may be necessary for fulminant hepatic failure. Encephalopathy, metabolic acidosis, hypoglycemia, and progressive rise in the prothrombin time are indications of severe liver injury.

B. Specific drugs and antidotes 1. If the serum level falls between the two nomogram lines,

consider giving NAC if the patient is at increased risk for toxicity; eg, the patient is alcoholic, malnourished or fasting or is taking drugs that induce P-450 2E1 activity [(eg, isoniazid (INH)]; after multiple or subacute overdoses; or if the time of ingestion is uncertain or unreliable.

2. If the serum level falls below the lower nomogram line, treatment is not indicated unless the time of ingestion is uncertain or the patient is considered to be at particularly high risk.

3. Note: After ingestion of extended-release tablets (eg, Tylenol Arthritis Pain™), which are designed for prolonged absorption, there may be a delay before the peak acetaminophen level is reached. This can also occur after co-ingestion of drugs that delay gastric emptying, such as opioids and anticholinergics. In such circumstances, repeat the serum acetaminophen level at 8 hours and possibly 12 hours. In such cases, it may be prudent to initiate NAC therapy before 8 hours while waiting for subsequent levels.

4. Duration of NAC treatment. The conventional US protocol for treatment of acetaminophen poisoning calls for 17 doses of oral NAC given over approximately 72 hours. However, for decades successful protocols in Canada, the United Kingdom, and Europe have utilized intravenous NAC for only 20 hours. In uncomplicated cases, give NAC (orally or IV) for 20 hours and follow hepatic transaminase levels and the PT/INR until 36 hours have passed since the time of ingestion. If

evidence of liver injury develops, NAC is continued until liver function tests are improving.

5. Chronic acetaminophen ingestions: Patients may give a history of several doses taken over 24 hours or more, in which case the nomogram cannot accurately estimate the risk of hepatotoxicity. In such cases, we advise NAC treatment if the amount ingested was more than 150–200 mg/kg or 6–7 g within a 24-hour period, if liver enzymes are elevated, or if the patient falls within a high-risk group. Treatment may be stopped 24–36 hours after the last dose of acetaminophen if liver enzymes and PT/INR are normal.

C. DecontaminationAdminister activated charcoal orally if conditions are

appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly.

1. Although activated charcoal adsorbs some of the orally administered antidote N-acetylcysteine, this effect is not considered clinically important.

2. Do not administer charcoal if more than 3–4 hours has passed since ingestion unless delayed absorption is suspected

D. Enhanced eliminationHemodialysis effectively removes acetaminophen from the

blood but is not generally indicated because antidotal therapy is so effective.

Dialysis should be considered for massive ingestions with very high levels (eg, >1000 mg/L) complicated by coma and/or hypotension.

2. Aspirin

The most widely used antiplatelet agent worldwide is aspirin. As a cheap and effective antiplatelet drug, aspirin serves as the foundation of most antiplatelet strategies.

Mechanism of Action

Aspirin produces its antithrombotic effect by irreversibly acetylating and inhibiting platelet cyclooxygenase (COX)-1 a critical enzyme in the biosynthesis of thromboxane A2.

At high doses (~1 g/d), aspirin also inhibits COX-2, an inducible COX isoform found in endothelial cells and inflammatory cells.

In endothelial cells, COX-2 initiates the synthesis of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation.

Site of action of antiplatelet drugs.

Aspirin inhibits thromboxane A2 (TXA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TXA2 release attenuates platelet activation and recruitment to the site of vascular injury. Ticlopidine and

clopidogrel irreversibly block P2Y12, a key ADP receptor on the platelet surface. Therefore, these agents also attenuate platelet recruitment. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen binding to activated glycoprotein (GP) IIb/IIIa.

COX-2 inhibitors were developed to block the production of inflammatory prostaglandins without affecting platelet function. The various COX-2 inhibitors differ in their selectivity for COX-2 relative to COX-1.

By blocking prostacyclin synthesis without concomitant inhibition of thromboxane A2 production, highly selective inhibitors of COX-2 increase the risk of cardiovascular events.

Thus, long-term rofecoxib therapy increases the risk of myocardial infarction (MI) three- to fivefold, a finding that led to the withdrawal of this drug from the market.

Indications Aspirin is widely used for secondary prevention of

cardiovascular events in patients with coronary artery, cerebrovascular, or peripheral vascular disease.

Compared with placebo, aspirin produces a 25% reduction in the risk of cardiovascular death, MI, or stroke. Aspirin is also used for primary prevention in patients whose estimated annual risk of MI is >1%, a point where its benefits are likely to outweigh harms.

This includes patients over the age of 40 with two or more major risk factors for cardiovascular disease or those over the age of 50 with one or more such risk factor.

Aspirin is equally effective in men and women. In men, aspirin mainly reduces the risk of MI, while in women aspirin lowers the risk of stroke.

Dosages Aspirin is usually administered at doses of 75–325 mg once

daily. Higher dose aspirin is not more effective than lower aspirin doses, and some analyses suggest reduced efficacy with higher doses.

Because the side effects of aspirin are dose-related, daily aspirin doses of 75–100 mg are recommended for most indications.

When rapid platelet inhibition is required, an initial aspirin dose of at least 160 mg should be given.

Side Effects Most common side effects are gastrointestinal and range from

dyspepsia to erosive gastritis or peptic ulcers with bleeding and perforation.

These side effects are dose-related. Use of enteric-coated or buffered aspirin in place of plain aspirin does not eliminate the risk of gastrointestinal side effects. The overall risk of major bleeding with aspirin is 1–3% per year.

The risk of bleeding is increased when aspirin is given in conjunction with anticoagulants, such as warfarin. When dual therapy is used, low-dose aspirin should be given (75–100 mg daily).

Eradication of Helicobacter pylori infection and administration of proton pump inhibitors may reduce the risk of aspirin-induced gastrointestinal bleeding in patients with peptic ulcer disease.

Aspirin should not be administered to patients with a history of aspirin allergy characterized by bronchospasm. This problem occurs in ~0.3% of the general population but is more common in those with chronic urticaria or asthma, particularly in individuals with nasal polyps or chronic rhinitis. Hepatic and renal toxicity are observed with aspirin overdose.

Aspirin Resistance Clinical aspirin resistance is defined as the failure of aspirin to

protect patients from ischemic vascular events. This is not a helpful definition because it is made after the event occurs.

Furthermore, it is not realistic to expect aspirin, which only blocks thromboxane A2–induced platelet activation, to prevent all vascular events.

Aspirin resistance has also been described biochemically as failure of the drug to produce its expected inhibitory effects on tests of platelet function, such as thromboxane A2 synthesis or arachidonic acid–induced platelet aggregation.

However, the tests of platelet function used for diagnosis of biochemical aspirin resistance have not been well standardized. Furthermore, these tests are not proven to identify patients at risk of recurrent vascular events.

3. Ibuprofen

GENERIC NAME: ibuprofen

BRAND NAME

Advil, Children's Advil/Motrin, Medipren, Motrin, Nuprin, PediaCare Fever etc.

DRUG CLASS AND MECHANISM Ibuprofen belongs to a class of drugs called non-steroidal anti-

inflammatory drugs (NSAIDs). Other members of this class include aspirin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and several others.

These drugs are used for the management of mild to moderate pain, fever, and inflammation. Pain, fever, and inflammation are promoted by the release in the body of chemicals called prostaglandins.

Ibuprofen blocks the enzyme that makes prostaglandins (cyclooxygenase), resulting in lower levels of prostaglandins. As a consequence, inflammation, pain and fever are reduced.

PREPARATIONS Tablets of 200, 400, 600, and 800 mg; Chewable tablets of 50 and 100 mg; Capsules of 200 mg; Suspension of 100 mg/2.5 ml and 100 mg/5 mlOral drops of 40 mg/ml.

STORAGE Ibuprofen should be stored at room temperature, between 15-

30°C (59-86°F).

PRESCRIBED FOR Ibuprofen is used for the treatment of mild to moderate pain,

inflammation and fever caused by many and diverse diseases.

DOSING For minor aches, mild to moderate pain, menstrual cramps,

and fever, the usual adult dose is 200 or 400 mg every 4 to 6 hours. Arthritis is treated with 300 to 800 mg 3 or 4 times daily.

When under the care of a physician, the maximum dose of ibuprofen is 3.2 g daily. Otherwise, the maximum dose is 1.2 g daily.

Individuals should not use ibuprofen for more than 10 days for the treatment of pain or more than 3 days for the treatment of a fever unless directed by a physician.

Children 6 months to 12 years of age usually are given 5-10 mg/kg of ibuprofen every 6-8 hours for the treatment of fever and pain. The maximum dose is 40 mg/kg daily.

Juvenile arthritis is treated with 20 to 40 mg/kg/day in 3-4 divided doses.

Ibuprofen should be taken with meals to prevent stomach upset.

DRUG INTERACTIONS Ibuprofen is associated with several suspected or probable

interactions that can affect the action of other drugs. Ibuprofen may increase the blood levels of lithium (Eskalith) by reducing the excretion of lithium by the kidneys.

Increased levels of lithium may lead to lithium toxicity. Ibuprofen may reduce the blood pressure-lowering effects of drugs that are given to reduce blood pressure.

This may occur because prostaglandins play a role in the regulation of blood pressure.

When ibuprofen is used in combination with aminoglycosides [for example, gentamicin (Garamycin)] the blood levels of the aminoglycoside may increase, presumably because the elimination of aminoglycosides from the body is reduced.

PREGNANCY There are no adequate studies of ibuprofen in pregnant

women. Therefore, ibuprofen is not recommended during pregnancy.

Ibuprofen should be avoided in late pregnancy due to the risk of premature closure of the ductus arteriosus in the fetal heart..

NURSING MOTHERS Ibuprofen is not excreted in breast milk. Use of ibuprofen while

breastfeeding, poses little risk to the infant.

SIDE EFFECTS The most common side effects from ibuprofen are rash, ringing

in the ears, headaches, dizziness, drowsiness, abdominal pain, nausea, diarrhea, constipation and heartburn.

NSAIDs reduce the ability of blood to clot and therefore increase bleeding after an injury.

Ibuprofen may cause ulceration of the stomach or intestine, and the ulcers may bleed.

Sometimes, ulceration can occur without abdominal pain, and black, tarry stools, weakness, and dizziness upon standing (orthostatic hypotension) due to bleeding may be the only signs of an ulcer.

NSAIDs reduce the flow of blood to the kidneys and impair function of the kidneys. The impairment is most likely to occur in patients who already have impaired function of the kidney or congestive heart failure, and use of NSAIDs in these patients should be cautious.

People who are allergic to other NSAIDs, including aspirin, should not use ibuprofen. Individuals with asthma are more likely to experience allergic reactions to ibuprofen and other NSAIDs.

Fluid retention (edema), blood clots, heart attacks, hypertension and heart failure have also been associated with the use of NSAIDs.

Mucolytic Carbocysteine Bromhexine Acetylcysteine

1. Karbotsistein (carbocysteine)

Synonyms Bronkatar, Bronhobos, Bronhokod, Drill otharkivayuschy,

Mukodin, Mukopront, Mukosol, Fluifort, Flyuvik, Flyuditek, Actithiol, Anatac, Broncatar, Bronchipect, Bronchocod, Caltusine, Carsitil, Drill expectorant, Ectofus, Flemex, Fluditec, Fluifort, Fluvic, Karbocistein, Lagan, Lisomucil, Mucifan, Mucodyne, Mucolase, Mucolisil, Mucolit, Mucopront, Mucosol, Pectox, Pneumoclar and others.

Applied lung disease involving accumulation viscous sputum (acute and chronic bronchitis, traheobronhity, asthma and bronchitis etc.), with middle ear inflammatory diseases and sinusal nose, as well as in preparation for tomography and bronhografii.

Assign into adults and 1 canteen spoon syrup 5% (0.75 g) 3 times a day for 1-2 or 2-3 capsules twice a day (depending on the current process and performance).

Children under 2 year teaspoon 2.5% syrup 2 times a day, from 2 year to 5 years and 1 teaspoonful of 2.5% syrup 2 times a day, 5 years and over-1 teaspoonful of 5% syrup, or 2 tea spoons 2.5% syrup 3 times a day.

The drug is usually well. In some cases, possible nausea, vomiting, diarrhea, gastrointestinal bleeding, allergic reactions (skin rashes, swelling Kvinke etc.).

Contraindications Karbotsistein contraindications to gastric ulcers and duodenal

ulcer in the process of being increased, disrupting kidney function, in the first trimester of pregnancy.

Enhance of glucocorticosteroids and teofillina; Protivokashlevye and atropinopodobnye drugs weaken karbotsisteina effect.

Method of production

2.5% syrup for children in bottles of 100, 125 and 200 ml, 5% in syrup bottles of 100, 110, 125, 150, 200 and 300 ml, or 9%, to 100 ml;

Capsules of 0, 375 g (N. 8, 10, 20); Chewing pill to 0.75 g (N. 20); Granules bags to 5 g (2.7 g).

2. Bromhexine

Bromhexine is a mucolytic agent used in the treatment of respiratory disorders associated with viscid or excessive mucus. In addition, bromhexine has antioxidant properties.

Brand names Bisolvon Forte - link International website Bisolvon.comHoesttabletten Bromhexine HClPaxirasolBarkacinVasicanBisolex

Function Bromhexine supports the body's own natural mechanisms for

clearing mucus from the respiratory tract.It is secretolytic: that is, it increases the production of serous

mucus in the respiratory tract and makes the phlegm thinner and less sticky.

This contributes to a secretomotoric effect: it helps the cilia - tiny hairs that line the respiratory tract - to transport the phlegm out

of the lungs. For this reason it is often added to some antitussive (cough) syrups.

Bromhexine is a synthetic derivative of the herbal active ingredient vasicine. It has been shown to increase the proportion of serous bronchial secretion, making it more easily to be expectorated.

Bromhexine also enhances mucus transport by reducing mucus viscosity and by activating the ciliated epithelium.

In clinical studies, Bromhexine showed secretolytic and secretomotoric effects in the bronchial tract area which facilitates expectoration and eases cough.

It is indicated as “secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport”.

Bromhexine is contained in various formulations, high and low strength syrups 8mg/5ml, 4 mg/5ml, tablets and soluble tablets (both with 8 mg bromhexine) and solution for oral use 10 mg/ 5 ml), adapted to the need of the patients.

The posology varies with the age, but there are products for all age groups from infant on.

Bromhexine is a well established and well tolerated product in its indication.

3. Acetylcysteine (N-Acetylcysteine [NAC])

Pharmacology Acetylcysteine (N-acetylcysteine [NAC]) is a mucolytic agent

that acts as a sulfhydryl group donor, substituting for the liver's usual sulfhydryl donor, glutathione.

It rapidly binds (detoxifies) the highly reactive electrophilic intermediates of metabolism or it may enhance the reduction of the toxic intermediate, NAPQI, to the parent, acetaminophen.

It is most effective in preventing acetaminophen-induced liver injury when given early in the course of intoxication (within 8 to 10 hours), but may also be of benefit in reducing the severity of liver injury by several proposed mechanisms (improved blood flow and

oxygen delivery, modified cytokine production, free radical or oxygen scavenging) even when given after 24 hours.

This proposed role of NAC as a glutathione precursor, direct sulfhydryl binding agent, and antioxidant has also been the basis for its investigational use for poisonings from agents associated with a free radical or oxidative stress mechanism of toxicity or that bind to sulfhydryl groups.

It may be used empirically when the severity of ingestion is unknown or serum concentrations of the ingested drug are not immediately available.

Indications A. Acetaminophen overdose.B. Case reports of or investigational use in carbon

tetrachloride, chloroform, acrylonitrile, doxorubicin, arsenic, gold, amanitin mushroom, carbon monoxide, chromium, cyanide, paraquat, and methyl mercury poisoning.

C. Pennyroyal oil and clove oil poisoning (case reports). The mechanism of hepatic injury by pennyroyal oil and clove oil are similar to that of acetaminophen, and empiric use of NAC seems justified for any significant pennyroyal oil or clove oil ingestion.

D. Cisplatin nephrotoxicity and prevention of radiocontrast-induced nephropathy.

Contraindications Known acute hypersensitivity or IgE-mediated anaphylaxis

(rare). Anaphylactoid reactions, while similar in clinical effects, may be prevented or ameliorated.

Adverse effects A. Acetylcysteine typically causes nausea and vomiting when

given orally. If the dose is vomited, it should be repeated. The dose calculation and proper dilution (to 5%) should be verified (this effect may be dose and concentration dependent). Use of a gastric tube, slower rate of administration, and a strong antiemetic agent

B. Rapid intravenous administration can cause flushing, rash, angioedema, hypotension, and bronchospasm (anaphylactoid reaction).

Death (status epilepticus, intracranial hypertension) was reported in a 30-month-old child accidentally receiving a massive dose intravenously (2,450 mg/kg over 6 hours, 45 minutes), and fatal bronchospasm occurred in an adult with severe asthma.

Reactions might be reduced by giving each dose slowly (over at least 60 minutes) in a dilute (3–4%) solution (this effect is dose and concentration dependent) and exercising extreme caution in asthmatics (avoid IV use or carefully titrate with more dilute solutions and slower infusion rates).

If an anaphylactoid reaction occurs, stop the infusion immediately and treat with diphenhydramine if urticaria and or angioedema is present, and epinephrine for more serious reactions (shock, bronchoconstriction).

Once symptoms have resolved, the infusion may be recommenced at a slower infusion rate (by further dilution and given over at least 1 hour

C. Use in pregnancy. There is no evidence for teratogenicity. Use of this drug to treat

acetaminophen overdose is considered beneficial to both mother and developing fetus. However, maternal hypotension or hypoxia due to a serious anaphylactoid reaction from IV administration may harm the fetus.

Drug or laboratory interactions A. Activated charcoal adsorbs acetylcysteine and may interfere

with its systemic absorption. When both are given orally together, data suggest that peak acetylcysteine levels are decreased by about 30% and that the time to reach peak level may be delayed. However, these effects are not considered clinically important.

B. NAC can produce a false-positive test for ketones in the urine.

Dosage and method of administration A. Oral loading dose. Give 140 mg/kg of the 10% (1.4 ml/kg) or 20% (0.7 ml/kg)

solution diluted to approximately 5% in juice or soda to enhance palatability: dilute the loading dose of 10% NAC with 1.4 mL/kg of juice or soda (for 20% NAC dilute with 2 mL/kg of juice/soda).

B. Maintenance oral dose. Give 70 mg/kg (as a 5% solution) every 4 hours. To make an approximately 5% solution, dilute the maintenance dose of 10% NAC (0.7 mL/kg) with 0.7 mL/kg of juice or soda (for 20% NAC dilute 0.35 mL/kg with 1 mL/kg of juice/soda).

The conventional protocol for treatment of acetaminophen poisoning in the United States calls for 17 doses of oral NAC given over approximately 72 hours. However, successful shorter protocols in Canada and Europe utilize intravenous NAC for only 20 hours for uncomplicated poisonings without evidence of liver injury treated within 8 hours of ingestion.

C. An intravenous preparation (Acetadote, Cumberland Pharmaceuticals) was approved in 2004 by the U.S. FDA and is indicated if the patient is unable to tolerate the oral formulation because of vomiting, ileus, intestinal obstruction, or other GI problems.

D. Dosage during dialysis. Although acetylcysteine is removed during dialysis, no change in dosage is necessary.

E. Dosage for prevention of radiocontrast-induced nephropathy. Give 600 mg of PO NAC twice on the day before and the day of the procedure (4 doses total).

This is coupled with IV hydration using 1/2 NS at 1 mL/kg/h for 12 hours before and after the administration of the contrast agent.

Formulations

A. Oral The usual formulation is as a 10% (100-mg/mL) or 20% (200-mg/mL) solution, supplied as an inhaled mucolytic agent (Mucomyst, or generic).

This form is available through most hospital pharmacies or respiratory therapy departments. This preparation is not FDA approved for parenteral use.

B. The new intravenous formulation (Acetadote) is available as a 20% solution in 30 mL (200 mg/mL) vials in a carton of 4 vials. Note: special precautions are needed to avoid accidental overdose or over-dilution with D5W in pediatric patients (see Table III–3 for IV Acetadote administration guidelines and precautions).

C. Suggested minimum stocking level for treatment of a 70-kg adult for the first 24 hours: 20% (oral) solution, 7 vials (30 mL each) and or 20% (IV) solution, 1 carton of 4 vials (30 ml each).

Actifed

USES Antihistamines provide relief of symptoms of allergies such as

rash, hives, watery eyes, runny nose, itching eyes and sneezing. Decongestants relieve congestion, promote sinus draining and improve breathing.

How To Use May be taken with food or milk to prevent

stomach upset. It is recommended to drink plenty of fluids while taking this

medication, unless doctor instructs otherwise. If symptoms do not improve after 7 days or are accompanied by a

high fever, notify doctor. Do not increase the dose or take this more frequently than

recommended.

Pharmacokinetics Because there is some evidence that chronic, excessive

consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol.

The manufacturers currently caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use acetaminophen or an alternative analgesic for self-medication because acetaminophen may increase the risk of hepatotoxicity.

However, the US Food and Drug Administration (FDA) has proposed eliminating this statement from the labeling of OTC acetaminophen-containing preparations and adding a new warning that would highlight the potential for severe liver damage to occur under certain circumstances, including in individuals who consume 3 or more alcohol-containing drinks per day while taking acetaminophen.

Absorption Pseudoephedrine is readily and almost completely absorbed

from the GI tract and there is no evidence of first-pass metabolism. Following oral administration of a 60- or 120-mg dose of

pseudoephedrine hydrochloride as an oral solution, peak plasma concentrations of about 180–300 or 397–422 ng/mL, respectively, were achieved in approximately 1.39–2 or 1.84–1.97 hours, respectively.

Absorption from extended-release preparations is slower and peak plasma concentrations of the drug are achieved in about 3.8–6.1 hours.

Following oral administration of single 30- or 60-mg doses of pseudoephedrine hydrochloride as a solution in pediatric patients (6–12 years of age), mean peak serum concentrations of 244 or 492

ng/mL, respectively, were achieved after 2.1 or 2.4 hours, respectively.

Food delays absorption of the drug when administered as a solution, but appears not to have an effect on absorption when the drug is administered as extended-release preparations.

Plasma pseudoephedrine concentrations of 274 ng/mL have been associated with a mean nasal decongestant response of 57.2%. After oral administration of 60 mg of pseudoephedrine hydrochloride as tablets or oral solution, nasal decongestion occurs within 30 minutes and persists for 4–6 hours.

Nasal decongestion may persist for 8 hours following oral administration of 60 mg and up to 12 hours following 120 mg of the drug in extended-release capsules.

Distribution Following oral administration of single 30- or 60-mg doses of

pseudoephedrine hydrochloride as a solution in children (6–12 years of age), the mean apparent volume of distribution at steady-state was 2.6 or 2.4 L/kg, respectively.

Although specific information is lacking, pseudoephedrine is presumed to cross the placenta and to enter CSF. Pseudoephedrine distributes into breast milk; about 0.5% of an oral dose is distributed into breast milk over 24 hours.

Elimination Pseudoephedrine is incompletely metabolized (less than 1%) in

the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in urine; 55–96% of a dose is excreted unchanged.

Urinary pH can affect the elimination half-life of pseudoephedrine, prolonging it when alkaline (pH 8) and reducing it when acidic (pH 5).

The elimination half-life of pseudoephedrine ranges from 3–6 or 9–16 hours when urinary pH is 5 or 8, respectively, while when

urinary pH is 5.8, the elimination half-life of the drug ranges from 5–8 hours.

In one study in children 6–12 years of age, the elimination half-life of pseudoephedrine averaged about 3 hours when urinary pH was 6.5. The rate of urinary excretion of pseudoephedrine is accelerated when urine is acidified to a pH of about 5 by prior administration of ammonium chloride. When the urine is alkalinized to a pH of about 8 by prior administration of sodium bicarbonate, some of the drug is reabsorbed in the kidney tubule and the rate of urinary excretion is slowed.

Renal clearance of pseudoephedrine is about 7.3–7.6 mL/minute per kg in adults.

Following oral administration of a single 30- or 60-mg dose of pseudoephedrine hydrochloride given as an oral solution in children 6–12 years of age, total body clearance was faster than that reported in adults, averaging about 10.3 or 9.2 mL/minute per kg, respectively.

Side Effects May cause drowsiness, dizziness, headache, loss of appetite,

stomach upset, blurred vision, restlessness, irritability and dry mouth and nose.

These effects should subside as your body adjusts to the medication. If they persist or become bothersome, inform your doctor.

Notify doctor if develop breathing difficulties, heart pounding, irregular heartbeat, chest pain, ringing in the ears, or difficulty urinating while taking this medication.

May cause dizziness especially when rising quickly from a seated or lying position.

Change positions slowly and be careful on stairs. Use caution engaging in activities requiring alertness.

Precautions

If have asthma, glaucoma, an ulcer, difficulty urinating due to an enlarged prostate gland, heart disease, high blood pressure, seizures, or an overactive thyroid gland, do not use this drug unless your doctor is aware of medical condition.

Check other medicines take for duplications. Do not drink alcoholic beverages. This drug should be used only if clearly needed during pregnancy. Consult doctor before breast-feeding. Do not give this medication to a child younger than six years of

age unless directed to do so by a doctor.

Missed Dose If you miss a dose, take as soon as remembered; do not take if it is

almost time for the next dose, instead, skip the missed dose and resume usual dosing schedule.

Do not "double-up" the dose to catch up.

Drug Interactions Tell doctor what medications that take, especially medication for

high blood pressure, seizures, or depression; sleeping pills, sedatives, tranquilizers, muscle relaxants, narcotic pain medication, other cold or allergy medication and of any other drugs may use, both prescription and nonprescription.

Do not take this drug if have taken an MAO inhibitor (e.g., furazolidone, phenelzine, selegiline, tranylcypromine) within the last two weeks.

Do not start or stop any medicine without doctor or pharmacist approval.