PHCT Chemo Drugs Reviewer(1) PDF

PHCT MIDTERMS Week 8: Chemotherapeutic Drugs Chemotherapeutic Drugs: o Dapsone o Amantadine o Quinine o Chloroquine and Aminoquinolines o Isoniazid ANTI-MICROBIALS The antibiotic class of drugs has proliferated immensely s...

PHCT MIDTERMS Week 8: Chemotherapeutic Drugs Chemotherapeutic Drugs: o Dapsone o Amantadine o Quinine o Chloroquine and Aminoquinolines o Isoniazid ANTI-MICROBIALS The antibiotic class of drugs has proliferated immensely since the Diagnosis is usually based on the history of exposure. first clinical use of sulfonamide in 1936 and the mass production of o Specific levels: Serum levels are particularly useful for penicillin in 1941. predicting toxic effects of aminoglycosides (Kanamycin, o Co-trimoxazole is a combination of trimethoprim and Amikacin, Gentamicin) chloramphenicol, and vancomycin. sulfamethoxazole and is in a class of medications called o Other useful laboratory studies: CBC, electrolytes, glucose, sulfonamides. BUN and creatinine, liver function tests, urinalysis, In general, harmful effects have resulted from allergic reactions or methemoglobin level. inadvertent IV overdose. Serious toxicity from single acute ingestion V. Treatment is rare. Emergency and supportive measures. I. Mechanism of toxicity Specific drugs and antidotes: Depends on the agent. 1. Trimethoprim poisoning: Administer leucovorin (Wellcovorin, In some cases, toxicity is an extension of pharmacologic effects, Citrovorum factor, Folinic acid). allergic or idiosyncratic reactions. ▪ To treat unintentional folic acid antagonist overdose, II. Toxic dose leucovorin (derivative/analog of folic acid that helps Toxic dose is highly variable. restore normal folate levels) is usually given intravenously as soon as possible after the overdose Life-threatening reactions may occur after subtherapeutic doses in hypersensitive individuals. ▪ Trimethoprim inhibits the enzyme dihydrofolate reductase III. Clinical presentation ▪ Sulfonamides/Dapsone/para-aminosalicylic acid After acute overdose, most agents cause only nausea, vomiting, and inhibits the enzyme dihydropteroate synthase diarrhea. 2. Dapsone overdose: Administer methylene blue for IV. Diagnosis symptomatic methemoglobinemia. DAPSONE Antibiotic used to treat leprosy (Hansen's disease → infectious Chronic daily dosing of 100 mg has resulted in methemoglobin levels condition that causes nerve damage and disfiguring sores on your of 5-8%. skin) and rare dermatologic conditions Death has occurred with overdose of 1.4 g and greater. Prophylaxis against Pneumocystis carinii in patients with AIDS and other immunodeficiency disorders Persons with glucose-6-phosphate dehydrogenase (G6PD) Peak plasma levels occur between 4 and 8 hours after ingestion deficiency, congenital hemoglobin abnormalities, and underlying Metabolized by 2 primary routes–Undergo enterohepatic hypoxemia may experience greater toxicity at lower doses. recirculation Average elimination half-life is 30 hours after a therapeutic dose and as long as 77 hours after an overdose III. Clinical presentation I. Mechanism of toxicity Methemoglobinemia: Causes cyanosis and dyspnea (shortness of breath), may persist for several days. Patients appear cyanotic even Toxic effects are caused by the p-450 metabolites, including after receiving antidotal treatment methemoglobinemia, sulfhemoglobinemia, Heinz body hemolytic anemia. o Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin Methemoglobinemia: Dapsone metabolites oxidize the ferrous iron (metHb) in the blood. Methemoglobin is a form of hemoglobin hemoglobin complex to the ferric state. that does not bind oxygen. When its concentration is elevated Sulfhemoglobinemia: Dapsone metabolites sulfate the pyrrole in red blood cells, tissue hypoxia can occur. hemoglobin ring; an irreversible reaction, and there is no antidote Sulfhemoglobinemia: Decreases oxyhemoglobin saturation, Hemolysis: Due to depletion of intracellular glutathione by oxidative unresponsive to methylene blue. metabolites. No antidote available o Sulfhemoglobinemia is a rare condition in which there is II. Toxic dose excess sulfhemoglobin (SulfHb) in the blood. The pigment is a greenish derivative of hemoglobin which cannot be converted Therapeutic ranges from 50-300 mg/d. 7 PHCT MIDTERMS back to normal, functional hemoglobin. It causes cyanosis o methylene blue acts to reduce the heme group from even at low blood levels. methemoglobin to hemoglobin Hemolysis: Heinz bodies may be seen; hemolysis may be delayed in Decontamination: onset 2-3 days after ingestion. o Prehospital: Administer activated charcoal Ipecac-induced IV. Treatment emesis for initial treatment Emergency and supportive measures. o Hospital: Administer activated charcoal and cathartic Specific drugs and antidotes: Methylene blue for Enhanced elimination: methemoglobinemia. o Repeat-dose activated charcoal ▪ Interrupts enterohepatic recirculation and is very o Methylene blue is indicated in the symptomatic patient with a effective methemoglobin level greater than 15% or with lower levels if ▪ Reduces half-life from 77 to 13.5 hours even minimal compromise of oxygen-carrying capacity is ▪ Continue charcoal for at least 48-72 hours potentially harmful o Charcoal hemoperfusion o Owing to its reducing agent properties, methylene blue is ▪ Reduces the half-life to 1.5 hours employed as a medication for the treatment of ▪ Effective in a sever intoxication unresponsive to methemoglobinemia conventional treatment AMANTADINE Effective in the treatment of Parkinson’s disease → a brain disorder to specific pharmacologic therapy with dantrolene → directly that causes unintended or uncontrollable movements interferes with muscle contraction by inhibiting calcium ion release characterized by a reduction in dopamine levels resulting in muscle relaxation Prophylaxis against parkinsonian side effects of neuroleptic agents Decontamination: Used in therapy of cocaine addiction Antiviral agent, amantadine (Symmetrel) o Prehospital: Administer activated charcoal Ipecac-induced emesis for initial treatment I. Mechanism of toxicity o Hospital: Administer activated charcoal and cathartic Enhances the release of dopamine and prevents dopamine reuptake in the peripheral and CNS Enhanced elimination: Not effective by dialysis. Has anticholinergic properties, especially in overdose. Amantadine is not effectively removed by dialysis, because the volume of distribution is very large (5 L/kg). The serum elimination II. Toxic dose half-life ranges from 12 hours to 34 days, depending on renal Not determined. Depends on kidney function. function o Elderly patients with renal insufficiency may develop toxic o drugs with a high degree of protein binding and large volume intoxication with the therapeutic doses of distributions are not efficiently eliminated by hemodialysis or hemoperfusion III. Clinical presentation Agitation, visual hallucinations, nightmares, tremor, disorientation, delirium, slurred speech, ataxia, myoclonus, seizures, heart failure, Anticholinergic manifestations (→ dry mouth, urinary retention, mydriasis), ventricular arrhythmias. Amantadine withdrawal may result in o Hyperthermia o Rigidity IV. Diagnosis Based on history of acute ingestion and symptoms. Specific levels not readily available. Serum levels above 1.5mg/L have been associated with toxicity. Other useful laboratory studies: Electrolytes, BUN, creatinine, ECG monitoring. V. Treatment Emergency and supportive measures. No known antidote. Treat tachyarrhythmias with beta-blockers such as propranolol or esmolol. Neuroleptic malignant syndrome → can occur in response to antipsychotic medications. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate (NMS) require surgent cooling measures and may respond 8 PHCT MIDTERMS QUININE Optical isomer of quinidine, used for treatment of malaria and for IV. Diagnosis chloroquine-resistant cases Based on history of ingestion and presence of cinchonism (a cluster The bark of the cinchona tree is used to make quinine. of dose-related and reversible side effects of quinine, including tinnitus, decreased hearing, headache, nausea, vomiting, dysphoria Treatment of nocturnal muscle cramps and visual disturbances caused by an overdose of quinine or its Also used as an abortifacient natural source, cinchona bark) and visual disturbances. I. Mechanism of toxicity Specific levels: Plasma quinine levels above 10 mg/L associated Toxic effects include retinal toxicity, photoreceptor and ganglion cell with visual impairment, levels above 20 mg/L with blindness, levels toxicity. above 16 mg/L with cardiac toxicity. II. Toxic dose Other useful laboratory studies: CBC, electrolytes, glucose, BUN, creatinine, arterial blood gases, ECG monitoring. Minimum toxic dose is approx. 3-4 g in adults. V. Treatment 1 g is fatal to a child. Emergency and supportive measures. III. Clinical presentation Specific drugs and antidotes: hypertonic sodium bicarbonate 1- Mild intoxication: Nausea, vomiting, cinchonism (tinnitus, deafness, 2meq/kg rapid IV bolus for cardiotoxicity. vertigo, headache, visual disturbances). Stellate ganglion block has previously been recommended for Severe intoxication: Ataxia, obtundation (a state similar to lethargy quinine-induced blindness. in which the patient has a lessened interest in the environment, slowed responses to stimulation, and tends to sleep more than o A stellate ganglion block is an injection of local anesthetic in normal with drowsiness in between sleep states.), convulsions, the sympathetic nerve tissue of the neck. These nerves are a coma, respiratory arrest, cardiotoxicity. part of the sympathetic nervous system. The nerves are located on either side of the voice box, in the neck. Retinal toxicity: Occurs 9-10 hours after ingestion, blurred vision, impaired color perception, constriction of visual fields, blindness, Decontamination: Activated charcoal and cathartic (induce macular edema, disk pallor. Pupils are fixed and dilated, retinal defacation). artery spasm Enhanced elimination: Acidification of urine may slightly increase Other toxic effects: Hypokalemia, hypoglycemia, hemolysis, renal excretion but does not significantly alter the overall elimination congenital malformations in pregnancy. rate. CHLOROQUINE AND AMINOQUINOLINES Used for prophylaxis or therapy of malaria and other parasitic Severe overdose: Convulsions, coma (avoid inducing vomiting with diseases, as well as rheumatoid arthritis. Chloroquine and ipecac or administering emetics in patients experiencing coma or hydroxychloroquine seizures), shock, respiratory or cardiac arrest, quinidine-like cardiotoxicity, severe hypokalemia. Drugs: Chloroquine phosphate (Aralen®), amodiaquine HCl (Camoquin®), hydroxychloroquine sulfate (Plaquenil®), mefloquine Severe chloroquine overdose may cause: (Lariam®), primaquine phosphate, quinacrine HCl (Atabrine®). o Quinidine-like cardiotoxicity may be seen including I. Mechanism of toxicity ▪ Sinoatrial arrest Chloroquine blocks DNA and RNA synthesis and has quinidine-like ▪ Depressed myocardial contractility cardiotoxicity. ▪ QRS or QT interval prolongation Primaquine and quinacrine can cause methemoglobinemia or hemolytic anemia (a disorder in which red blood cells are destroyed ▪ Heart block epinephrine faster than they can be made. The destruction of red blood cells is ▪ Ventricular arrhythmias called hemolysis), especially in G6PD-deficient patients. glucose-6- phosphate dehydrogenase (G6PD) enzyme. G6PD helps red blood Severe hypokalemia cells work and protects them from harmful substances and Primaquine and quinacrine intoxication: GIT upset, severe premature destruction. G6PD deficiency → hemolytic anemia methemoglobinemia, hemolysis, ototoxicity, retinopathy. II. Toxic dose Amodiaquine: Fatal neutropenia. Therapeutic dose of chloroquine phosphate is 500 mg once a week Mefloquine: Dizziness, vertigo, hallucinations, psychosis, seizures. for malaria prophylaxis, or 2.5 g over 2 days for malaria treatment. IV. Diagnosis Deaths reported in children after doses as low as 300 mg; lethal dose Specific levels: Chloroquine levels can be measured in blood but are for adults estimated at 30-50 mg/kg. not generally available. III. Clinical presentation Other useful laboratory studies: Electrolytes, glucose, BUN, Mild to moderate overdose: Dizziness, nausea, vomiting, abdominal creatinine, ECG monitoring. For primaquine or quinacrine, also pain, headache, visual disturbances, auditory disturbances, include CBC, free plasma hemoglobin, methemoglobin. agitation, neuromuscular excitability. 9 PHCT MIDTERMS V. Treatment Enhanced elimination: Ineffective. Emergency and supportive measures. Specific drugs and antidotes: e1-2meq/kg IV Sodium bicarbonate for cardiotoxicity, epinephrine infusion for hypotension, high-dose diazepam (2mg/kg IV, given over30mins) for cardiotoxicity. Decontamination: Activated charcoal and ipecac-induced emesis for initial treatment. ISONIAZID (INH) Hydrazide derivative of isonicotinic acid Hepatitis Bactericidal drug choice for tuberculosis Hypersensitivity reactions like lupus erythematosus and pyridoxine Known to cause hepatitis on chronic use deficiency Drug-induced seizures and metabolic acidosis on acute isoniazid overdose IV. Diagnosis I. Mechanism of Toxicity Usually made by history and clinical presentation. A. Acute Overdose INH should be considered in any patient with acute onset seizures, especially when accompanied by profound metabolic acidosis. Competes with pyridoxal 5-phosphate (active form of Vit. B6) for glutamic acid decarboxylase. A. Specific Levels Lower levels of GABA lead to uninhibited electrical activity A 5 mg/kg dose produces a peak INH concentration of 3 mg/L at 1 manifested as seizures. hour. Also inhibits hepatic conversion of lactate to pyruvate, resulting in Serum levels higher than 30 mg/L are associated with acute toxicity. lactic acidosis. B. Other Useful Laboratory Studies B. Chronic Toxicity Electrolytes Competes with pyridoxine (vitamin B6), resulting in peripheral Glucose neuritis. BUN II. Toxic Dose Creatinine A. Acute Ingestion Liver function tests (for chronic toxicity) Ingestion of as little as 1.5 g can produce toxicity. Arterial blood gases Severe toxicity is common after ingestion of 80-150 mg/kg. V. Treatment B. Chronic Use A. Emergency and Supportive Measures 10-20% of patients will develop hepatic toxicity when the dose is 10 mg/kg/day. B. Specific Drugs and Antidotes Less than 2% will develop this toxicity if the dose is 3-5 mg/kg/day. Pyridoxine (vitamin B6) terminates diazepam-resistant seizures. Older persons are more susceptible to chronic toxicity. C. Decontamination III. Clinical Presentation Prehospital A. Acute Overdose Administer activated charcoal. Slurred speech Do not induce emesis because of the risk of rapid onset of coma and seizures. Ataxia Hospital Coma Administer activated charcoal and cathartic. Seizures Gastric lavage for massive ingestions. Hemolysis D. Enhanced Elimination B. Chronic Therapeutic INH Use Forced diuresis and dialysis. Peripheral neuritis 10