PHCT Analgesic Drugs Reviewer PDF

PHCT MIDTERMS Week 7: Analgesic Drugs ACETAMINOPHEN Acetaminophen (Biogesic, Tempra, Tylenol) is a widely used drug After 24-48 hours: prothrombin time (measures the time it takes for found in many over the counter and prescription analgesics and cold the pla...

PHCT MIDTERMS Week 7: Analgesic Drugs ACETAMINOPHEN Acetaminophen (Biogesic, Tempra, Tylenol) is a widely used drug After 24-48 hours: prothrombin time (measures the time it takes for found in many over the counter and prescription analgesics and cold the plasma of blood to clot) and transaminase levels rise, hepatic remedies. necrosis is evident. (Increased transaminase levels: ALT (alanine transaminase) and AST (aspartate transaminase) → liver damage → Active metabolite of phenacetin and is responsible for its analgesic hepatic necrosis effect. If acute hepatic failure occurs, hepatic encephalopathy (liver It is a weak (cyclooxygenase) COX-1 and COX-2 inhibitor. dysfunction → accumulation of neurotoxic substance → Adults: sulfation, glucuronidation bloodstream → CNS - CNS manifestations: confusion, slurred Children: sulfation speech, decreased cognitive function) and death may ensue, acute renal failure. Mechanism of toxicity: Diagnosis: Overdose of acetaminophen metabolite exceeds glutathione capacity, and the metabolite reacts with hepatic macromolecules, Specific levels: Obtain a 4-hour post-ingestion acetaminophen level causing liver injury. and use the nomogram to predict the range of severity. Active metabolite is N-acetyl-p-benzoquinone imine. Falsely elevated acetaminophen levels may occur in the presence of high levels of salicylate and other interference by certain methods. Same mechanism occurs in renal damage owing to renal metabolism. Other useful laboratory studies: Electrolytes, Glucose, BUN, Creatinine, Liver transaminases, Prothrombin time. Overdose during pregnancy has been associated with fetal death and spontaneous abortion (Pregnancy Category B) → Animal Treatment: reproduction studies have failed to demonstrate a risk to the fetus Emergency and supportive measures: and there are no adequate and well-controlled studies in pregnant o Spontaneous vomiting may delay the administration of women. antidote and charcoal and should be treated with Toxic dose: metoclopramide. Acute ingestion of more than 140 mg/kg in children or 6 g in adults is o Liver transplant may be necessary for massive hepatic failure. potentially hepatotoxic. Specific drugs and antidotes: Children < 10-12 years old are less susceptible due to the smaller o If the serum level falls above the lower line on the nomogram contribution of cytochrome P-450 to acetaminophen metabolism. or if stat serum levels are not immediately available, start Chronic alcoholics and patients with induced cytochrome P-450 antidotal therapy with acetylcysteine, 140 mg/kg orally. have lower margin of safety (prone to poisoning) because of the o Antidote for acetaminophen poisoning: N-acetylcysteine possible production of more toxic metabolites. (causes depletion of (mucolytic, precursor of glutathione (cysteine) → increases glutathione) production of glutathione to metabolize/decrease NAPQI Chronic toxicity has been reported after daily consumption of high Decontamination: therapeutic doses by alcoholics. o Prehospital: Administer activated charcoal, if available. Toxicity: increased NAPQI → decreased glutathione (react to hepatic Ipecac-induced emesis may be useful for initial treatment of cells causing injury) glutathione detoxifies the toxic metabolite of children at home if it can be given within 30 minutes of paracetamol, NAPQI exposure. Fatal dose: o Hospital: Administer activated charcoal and a cathartic. Ingestion of 15 g of acetaminophen may be fatal, death being caused Gastric emptying is not necessary if charcoal can be given by severe hepatotoxicity with centrilobular necrosis (cell death → promptly. death of hepatocytes which are liver cells), sometimes associated o "It is not allowed to administer ipecac and activated charcoal with acute renal tubular necrosis. at the same time." Clinical presentation: Enhanced elimination: Hemoperfusion (undergoes an adsorbent Early after acute acetaminophen overdose: Anorexia, material such as activated charcoal and synthetic resins) removes Nausea/Vomiting. acetaminophen from blood effectively (but is not generally indicated because of activated charcoal’s efficacy SALICYLATES Salicylates are widely used for their analgesic and anti-inflammatory 1981 – aspirin recognized for preventing second heart attacks properties. 1998 – aspirin 81mg launched 2001 – aspirin used within 4 hours of heart attack can reduce risk of They are found in a variety of prescription and over-the-counter fatality by up to 25% analgesics, cold preparations, and topical keratolytic products 2002 – aspirin recognized by Health Canada as preventing first non- (methyl salicylate), and even Pepto-Bismol (bismuth subsalicylate). fatal heart attacks 4 indications of aspirin: anti-inflammatory, analgesic, antipyretic, Before the introduction of child-resistant containers, salicylate antiplatelet (inhibits platelet aggregation) overdose was one of the leading causes of accidental death in History – Salicylates children. 1897 – ASA developed 1915 – aspirin distributed to doctors, becomes #1 drug worldwide 4 PHCT MIDTERMS Mechanism of toxicity: o Chronic intoxication: Chronic therapeutic concentrations in arthritis patients range from 100 to 300 mg/L (10-30 mg/dL). A Salicylates have a variety of toxic effects: level greater than 600 mg/L (60 mg/dL) accompanied by o Hyperventilation leading to respiratory alkalosis (increased acidosis and altered mental status is considered very blood pH (alkaline/basic) due to loss of carbon dioxide from dangerous. lungs → decrease in carbonic acid) , metabolic acidosis Other useful laboratory studies: Electrolytes (anion gap calculation), (decreased blood pH because of buildups of acid such as glucose, BUN, creatinine, prothrombin time (PT), arterial blood lactate and ketones) contributing to dehydration (due to gases, chest x-ray. central stimulation of the respiratory center). Treatment: o Uncoupling of oxidative phosphorylation and interruption of glucose and fatty acid metabolism. Emergency and supportive measures: o Cerebral and pulmonary edema that may be related to o Maintain the airway and assist ventilation if necessary. alteration in capillary integrity. Administer supplemental oxygen. Obtain serial blood gases and chest x-rays to observe for pulmonary edema. o Platelet function is altered, and prothrombin time is prolonged. o Treat coma, seizures, pulmonary edema, and hyperthermia. Dose: o Treat metabolic acidosis with intravenous sodium bicarbonate. Do not allow the serum pH to fall below 7.4. Average therapeutic single dose: 10 mg/kg. o Replace fluid and electrolyte deficits caused by vomiting and Usual daily therapeutic dose: 40-60 mg/kg/d. hyperventilation with intravenous crystalloid solutions. Aspirin tablet: 325-650 mg acetylsalicylic acid. o Monitor asymptomatic patients for a minimum of 6 hours. Toxic dose: Admit symptomatic patients to an intensive care unit. Acute ingestion of 150-200 mg/kg will produce mild intoxication; Specific drugs and antidotes: acute ingestion of 300-500 mg/kg is likely to produce severe o There is no specific antidote for salicylate intoxication. intoxication. o Sodium bicarbonate is frequently given both to prevent Chronic intoxication may occur with ingestion of more than 100 acidemia and to promote salicylate elimination by the mg/kg/d for 2 or more days. kidneys. Clinical presentation: o Antidote for aspirin (acidic) poisoning: sodium bicarbonate Acute ingestion: (basic) o Vomiting after ingestion. Decontamination: o Hyperpnea, tinnitus (ringing of ears), and lethargy. o Prehospital: Administer activated charcoal. Ipecac-induced o Mixed respiratory alkalemia and metabolic acidosis. emesis for initial treatment of children. o Coma, seizures, hypoglycemia, hyperthermia, and pulmonary o Hospital: Administer activated charcoal and cathartic orally edema (severe intoxication). or by gastric tube. o Death caused by CNS failure and cardiovascular collapse. Enhanced elimination: o Salicylism (vomiting, tinnitus, decreased hearing, and o Urinary alkalinization: Effective in enhancing urinary excretion vertigo)—reversible by reducing the dosage. of salicylate. o Contraindicated to children with viral infection → Reye’s o Acidic drug – basic environment → ionized → easily excreted Syndrome (a rare condition that affects your brain, blood and in the urine. liver. It occurs among children who take aspirin to treat a viral o Acidic drug – acidic environment/ basic drug – basic infection.) → Fatal encephalopathy of the kidney and brain. environment → non-ionized → absorbed into the Chronic intoxication: bloodstream o Young children and confused elderly are the usual victims. o Hemodialysis: Very effective in rapidly removing salicylate and correcting acid-base and fluid abnormalities. Indications o Cerebral and pulmonary edema are more common with acute for hemodialysis include: intoxication. ▪ Patients with acute ingestion and serum levels > 1200 o Nonspecific confusion, dehydration, and metabolic acidosis mg/L (120 mg/dL), or with severe acidosis and other are attributed to sepsis, pneumonia, or gastroenteritis. manifestations of intoxication. Diagnosis: ▪ Patients with chronic intoxication with serum levels > Not difficult if there is a history of acute ingestion, accompanied by 600 mg/L (60 mg/dL) accompanied by acidosis, typical signs and symptoms. confusion, or lethargy, especially if the patient is elderly or debilitated. In the absence of a history of overdose, diagnosis is suggested by the characteristic arterial blood gases, which reveal a mixed respiratory o Hemoperfusion: Very effective but does not correct acid-base alkalemia and metabolic acidosis. or fluid disturbances. Specific levels: Obtain stat and serial serum salicylate o Repeat-dose activated charcoal therapy: Effectively reduces concentrations. Systemic acidemia increases brain salicylate serum salicylate half-life, but not as rapidly effective as concentration, worsening toxicity. dialysis, and frequent stooling may contribute to dehydration and electrolyte disturbances. o Acute ingestion (within 4 hrs): Salicylate levels are plotted on the nomogram to estimate toxicity. 5 PHCT MIDTERMS NSAIDs These are chemically diverse group of agents that share similar Oxyphenbutazone, phenylbutazone, mefenamic acid, piroxicam and pharmacologic properties and are widely used for control of pain ibuprofen overdose produce: and inflammation. o Seizures Overdose by most of the agents in this group usually produces only o Coma mild gastrointestinal upset. o Renal failure NSAIDS: COX inhibitors o Cardiorespiratory arrest Nonselective NSAIDs (mefenamic acid, ibuprofen, diclofenac): COX o Hepatic dysfunction 1 (production of prostaglandin (defensive factor of GIT) → o Hypoprothrombinemia perforation in GI tract) and COX 2 (production of leukotriene → no o Metabolic acidosis inflammation/pain) inhibition Diflunisal overdose produces same toxicity as with salicylate Ulcer pain reliever: selective COX 2 inhibitors poisoning. Indoleacetic acid Diagnosis: o Indomethacin o Sulindac Diagnosis is usually based primarily on a history of ingestion of o Tolmetin NSAIDs, because symptoms are mild and nonspecific and Pyrazoles quantitative levels are not usually available. o Phenylbutazone Other useful laboratory tests: CBC, electrolytes, glucose, BUN, o Oxyphenbutazone creatinine, liver transaminases, prothrombin time (PT), urinalysis Salicylates Treatment: o ASA o Diflunisal no antipyretic effect Emergency and supportive measures: o Methyl salicylate o Treat seizures, coma, and hypotension if they occur. Ketorolac alternative to morphine for nonsurgical procedures o Antacids may be used for mild GIT upset. Propionic Acid o Ibuprofen o Replace fluid losses with intravenous crystalloid solutions. o Naproxen Specific drugs and antidotes: o Ketoprofen Oxicams o There is no specific antidote for most NSAID overdoses. o Piroxicam o Vitamin K(phytonadione) (pro-coagulant) may be used for Fenamates patients with prothrombin time (PT) caused by o Mefenamic acid hypoprothrombinemia (deficiency of the blood-clotting o Meclofenamic acid substance prothrombin, resulting in a tendency to prolonged Mechanism of toxicity: bleeding) to enhance clotting Toxicity effects may be attributed to inhibition of cyclooxygenase Decontamination: CNS, hemodynamic, pulmonary, and hepatic dysfunction also occur o Prehospital: Administer activated charcoal if available. with some agents Ipecac-induced emesis may be considered for immediate Acute or chronic intoxication may affect gastric mucosa and renal treatment blood flow due to a decrease in prostaglandins o Hospital: Administer activated charcoal and a cathartic orally Toxic dose: or by gastric tube. Generally, intoxication occurs after ingestion of more than 5-10 Enhanced elimination: times the usual therapeutic dose o Hemodialysis and hemoperfusion are generally not effective Clinical presentation: in removing NSAIDs due to their high protein binding (highly NSAID overdoses are generally asymptomatic or have mild GIT upset protein bound) and large volume of distribution. (nausea, vomiting, abdominal pain, sometimes hematemesis o Charcoal hemoperfusion for phenylbutazone overdose may (vomiting of blood)). be effective. Occasionally patients exhibit drowsiness, lethargy, ataxia, nystagmus, tinnitus and disorientation. 6