Description
The presentation describes TDM or Therapeutic Drug Monitoring by analysing topics like purpose, Pharmacokinetic Considerations, Methodological Difficulties.
Therapeutic Drug monitoring
Therapeutic drug monitoring
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?
?
?
Involves the analysis, assessment and evaluation of circulating concentrations of drugs in serum, plasma, or whole blood. Purpose is to ensure the medication dose is at therapeutic range and not toxic. Medications dosage differ between each patient based on metabolic process. Therapeutic range is narrow for most drugs( below range drug not effective, above rang : drug toxic)
Biological effect
?
? 1. 2. 3.
4.
A drug is effective when it binds to a specific receptor in the target tissue. TDM assumes that serum levels are proportional to the intercellular tissue bind capacity of the drug. Drug utilization in the body is influenced by: Absorption Distribution Metabolism Excretion
Absorption
3 routes of administration for drugs to go through absorption. 1. Orally 2. Rectally 3. IV/IM Orally: drug is absorbed by the GI tract- the drugs are formulated to withstand acid pH in the stomach so that the medication can be absorbed in the intestine.
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Rectally: drug is absorbed within the And the lining of the lower intestine.
?
IV/IM: the drug is directly administered into the venous flow and absorbed into the tissue. Distribution of Drug: Once in the circulation most drugs are quickly distributed based on the solubility of the drug. Water-soluble vs. water insoluble (need protein carriers: albumin and Alpha1-scid glycoprotein.)
?
?
Theoretically: volume of body fluid needed to dissolve the total amount of drug required to achieve concentration found in the blood. Metabolism: drugs absorbed, distributed and excreted in urine or waste product. The liver metabolized the lipid insoluble drugs into more H2O soluble form. Enzymes in heptocytes help in the conversion of soluble gluconoride, sulfate and phosphate.
excretion
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?
?
Kidneys are the primary excretory organ. Renal disease: other excretory organs or pathway become involved such as: biliary tract, lungs and sweat glands. H2O soluble drugs excrete faster that insoluble. pH of urine is based on the acidic or basic nature of the drug.
Pharmokinectics
?
?
1.
2.
3. 4.
Mathematical model to predict plasma drug levels or their metabolites over a fixed period of time and dosage effects with the least toxic effect. Must consider: Drug elimination from the body is constant. Serum concentration is the same as drug effect. Body is considered a single compartment Distribution is uniform.
?
?
?
?
Process that assist in establishing and modifying a dose regimen. Dose response curve: single dose of medication taken by mouth, the drug response is based on it’s half-life (how long it takes to break down or be metabolized). Trough and Peak levels used to maintain levels. Half-life: time required for drug concentration to be reduced by half. If half life is long: patients metabolize and excreted drug slowly. If half life is short: patients metabolize and excretes drug quickly.
Total body clearance (TBC): 1. Predicts effective dosage 2. Rate of elimination of drug 3. Used to adjust dose and rate of medication. Drug effects: drugs are only effective if at therapeutic levels. Effective when it binds to a specific receptor or target tissue. TDM assumes levels are proportional to intracellular tissue binding to the drug.
?
Factors that effect serum drug levels
Patient compliance 2. Drug absorption 3. Protein binding 4. Enzyme induction Drug disposition: the characteristic of the drug effect how effective the drug is. Factors that affect the effectiveness of medications: Age, Pregnancy, diseases, and the drug itself.
1.
Age
? ?
?
?
Neonates vs. children vs. elderly Neonates: underdeveloped organs (liver/kidneys) and are not able to eliminate drugs as readily. Have to administer decreased doses. Children: (6-10), doses are doubled the adult dose, due to growth process and increased metabolism. Elderly: decrease in proteins, metabolism and renal function therefore easily reach toxic levels, have to decrease dose.
?
? 1. 2. 3.
Pregnancy: hormonal changes, GI emptying, increase body volume and protein concentration change all influence the way the drug is metabolized normally. Disease: Liver: decreases ability to metabolize and excrete. Cardiac: effects blood flow to the GI tract. Renal : problem with elimination and metabolism of drug.
Cardiac medication
? 1. •
• • •
Medication that is used to treat various heart diseases. Digoxin: cardiac glycoside used for CHF. Function by inhibiting membrane Na, K, ATPase. Cause increase calcium levels which improves cardiac contraction. Toxicity affects many organs and cell types. (nausea, vomiting, and visual problems) Absorption orally is variable and is influenced by dietary factors and formulation of the drug Elimination occurs by renal filtration
? 1.
2.
3.
Digoxin Serum levels are influenced by glomerulus filtrate rate. Concentration of electrolytes. (low K and Mg potentiate digoxin levels) Thyroid status (Hyper: resistant, Hypo: more sensitive)
Lidocaine
?
?
Used to correct ventricular arrhythmias and prevent ventricular fibrillation. Completely eliminated by the liver If orally given as monoethylglycinexylidide (MEGX).
Quinidine
?
? ?
?
Used to treat cardiac arrhythmic disorders in the form of quinidine sulfate fast half-life) and quinindine gluconate (slow half-life) Liver disease may extend half-life. Toxic effects see nausea, vomiting, and abdominal discomfort Eliminated by the liver.
Procainamide
? ?
?
? ?
?
Treats arrhythmic disease Absorbed by GI tract rapidly Eliminated by renal filtration and hepatic system. Major metabolite: N-acetylprocainamide (similar to procainamide) Increased concentration due to over dose or lack of elimination results in myocardial depression and arrhythmia. Assay: must differentiate the porcainamide from Nacetyl-procainamide.
Disopyramide
? ?
?
Used as a quinidine substitute Eliminated by renal filtration and some hepatic Toxicity symptoms: dry mouth and constipation.
Antibiotics
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?
?
?
Aminoglycosides: treat infection with gram negative bacteria. Gentamycin, tobramycin, amikacin, and kanamycin Toxicity involve; nephrotoxicity and ototoxcity (ear) and effects balance and hearing. Eliminated by renal system
Vancomycin
?
? ?
?
Glycopeptides: effective against Gram positive cocci and bacilli. Poor oral absorption, given IV. Toxicity: kidney, ototoxicity, Red-man syndrome( flushing of skin of the extremities) Eliminated by renal excretion
Antiepileptic drugs
Used to treat epilepsy, seizures and convulsions on a prophylactic bases. ? Phenobarbital: is a barbiturate that is absorb slow orally and has a long half-life. ? Primidone is its proform (inactive)- rapidly absorbed and converted into the active form.
?
? ?
?
Phenytoin (dilantin): used to treat seizure disorders and brain injury to prevent loss of functional tissue. Unbound form is the active form. Adverse effects: hirsutism, gingival hyperplasia, vitamin D, and folate def. Eliminated by hepatic metabolic process
Valporic Acid
? ? ? ? ?
Used petit mal and absence seizure. GI absorption is rapid and complete. Circulates protein bound (93%). Eliminated by hepatic system Nausea, lethargy and weight gain are most common adverse effect.
Carbamazepine
Used to treat various seizure disorders. ? Can cause serious toxic adverse effects ? Circulates protein bound (70-80 %) ? Eliminated primarily by hepatic metabolism. ? Any liver dysfunction can results in serum accumulation. Ethosuximide: used to control petit mal seizure, admin.
?
Psychoactive Drugs
?
Lithium: Used to treat manic-depression (bipolar disorder). Absorption is complete and rapid. Distribution is uniform throughout the body. Eliminated by renal function. Concentration levels 1.2-2 mmol/l cause apathy, lethargy, speech difficulty's and muscle weakness. Concentrations greater than 2.0 mmol/L may cause muscle rigidity, seizures and coma.
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Tricyclic antidepressants (TCS) used to treat depression, insomia, extreme apathy and loss of libido. Examples: imipramine, aminitriptyline, and doxepin. All have a variable degree of absorption. Circulate protein bound (85-95%). Therapeutic levels may take as longs as 2-4 weeks. Toxicity may cause drowsiness, constipation, blurred vision and memory loss.
Bronchodilators
?
Theophyline: used to treat asthma and chronic obstructive pulmonary diseases. Used in acute and prophylactic treatment. Absorb form circulates protein bound (50%). Eliminated by both renal and hepatic organs. Therapeutic range is narrow, toxicity include nausea, vomiting and diarrhea.
Immunosuppressive drugs
?
?
?
Used to prevent rejection in various organ transplantation procedures. Cyclosporin: cyclic polypeptide used to prevent GVHD or heterotrophic transplant organs. Tacrolimus: 100X more potent than cyclosporine, used in same manner just takes less medication.
Antineoplastics
? ?
Used to treat neoplastic disorders (cancer) Methotrexate: inhibits DNA synthesis in all cells.
Chapter 29 Toxicology
? ?
1.
2.
3. 4.
Stud of poisons. Four disciplines: Mechanistic: basis for rational therapy design and the development of tests. Descriptive: result of animal test to predict harmful effects to humans. Forensic Clinical diagnostics: diagnosis of interrelationships of toxins and disease states.
Exposure to toxins
? ? ? ?
Occurs by various routes: Suicide (50%) Accidental (30%) Rest are related to occupational exposure or homicide
Routes of exposure
? ? ?
Ingestion Inhalation Transdermal absorption
Dose-response relationship
?
? ?
?
Poison: any substance that causes a harmful effect upon exposure. Dose is a key issue. There are various toxic effects from drugs based on dose including death. Dose-response implies that there will be an increase in the toxic response as the dose is increased.
?
Acute toxicity: associated with a single, short term effect to a substance, the dose is sufficient to cause immediate toxic effect.
Chronic toxicity: associated with repeated exposure for extended periods, at a dose that are insufficient to cause immediate acute response.
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Analysis of toxic agents
Two-step procedure Screening test, which is a rapid , simple analysis that is qualitative procedure to detect specific classes or substance. Lack specificity. Tells us something is there just not specific to what. Confirmatory test: test utilizing more specificity- tells us what drug and how much. Methods: gas chromatography using mass spectrophotometer.
Specific agents
?
?
Alcohol: common depressant of the central nervous system. Perform Blood alcoholsalong with liver panel to evaluate toxicity. Methanol: common solvent ingested accidentally or from contaminant of homemade liquors. Death can occur due to the formation of formic acid leading to severe acidosis.
Isopropanol: rubbing alcohol, by product acetone. Both are CNS depressants ? Ethylene glycol: common component of anti-freeze. Causes crystallization of calcium oxalate within the renal system and cause tubular damage if dosage high. Determination: serum, plasma, whole blood used in correlation with psychomotor test for alcohol, do not use alcohol to clean area for venipuncture can contaminate. Analytical method enzymatic gas chromatography.
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?
?
?
?
Carbon monoxide: by product of incomplete combustion of carbon containing substances (gasoline engines, furnaces and wood or plastic fires.) Colorless, odorless and tasteless gas that is absorbed into the blood from inhaled air. Toxic effect is due to its affinity for divalent iron within heme (hgb, myoglobulin, etc). Hgb affinity has the most effect due to the production of carboxyhemoglobulin (245X greater affinity)
O2 and CO2 compete for the binding sites on the RBC, decrease O2 carrying capacity in the presence of CO2. ? Methods: 1. Spot test: using 5 ml of 40% NaOH mixed with 1/20 aqueous dilution of whole blood yielding a pink color if CO2 present at 20% or greater value ( CO2 produces a cherry red color compound) 2. Quantitative method (differential spectrophotometry and gas chromotography) Causative agent: occupational or household exposure of cleaning agents.
?
Cyanide
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?
?
?
?
Supertoxic substance that exist as a gas, solid or in solution. Exposure can occur through inhalation, ingestion, or transdermal absorption. Found in insecticides and rodenticides Toxic effect involves its ability to bind heme iron. Method for analysis: Ion specific electrode and photometric.
Metals
Arsenic: exist bound or as primary constitute of organic and inorganic compounds. • Found naturally and can be manmade forms. • Exposure through environment occurs around industries. • Absorption of arsenic depends on the form. • Toxicity related to the binding ability to protein. • Assay: atomic absorption spectrophotometry.
Cadium
?
? ? ?
Metal found in industrial processes (electroplating and galvanizing) Pigment found in paints and plastics. Significant environmental pollutant. Exposure occurs through inhalation, toxicity related to ability to bind to protein tends to accumulate in the kidney’s.
Lead
? ? ? ?
?
?
Common environmental contaminant Use to be used in household paint and gasoline. Exposure can occur in various route- most is through dietary ingestion of contaminated material. Toxicity related to ability to bind to macromolecular structures. Distributes into the bones and soft tissue in theory. Elimination occurs through the renal system. Lead toxicity has various physical effects (neurological, ADHD, ADD, decreased intelligence. Potent inhibitor of many enzymes (Vit. D, heme synthetic pathway) resulting in bone and calcium metabolism and in anemia.
?
?
Treatment involves using a therapeutic chelater such as EDTA and DMSA. Assay: chromogenic reaction and anodic stripping voltametry methods. Most common method AAS.
Mercury
? ? ?
?
?
Metal found in three forms: elemental, inorganic salts or organic compound. Exposure occurs through inhalation and ingestion (contaminated food) Each form vary in toxic effect. (organic is the most toxic) Toxicity related to ability to bind protein resulting in a change of structure and function. Inhibits a number of enzyme activities. Many biological effect most noted is renal. Assay: AAS
Pesticides
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Substance that are intentional used to kill or harm an undesirable life form. Categorized as insecticide and herbicides which are used to control of vector-borne disease and urban pest and to improve agricultural productivity. Contamination of food is the major route of exposure. Inhalation, transdermal absorption and ingestion through hand-to mouth contact are common occupational and accidental exposure.
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Actions of most are nonselective and result in toxic effect to various organs. Wide variation of pesticides that range from salts to heavy metals. Organophosphate and carvamates function by inhibition of acetylcholine esterase. Acetylcholine is a neurotransmitter and has many effects in the body. Test utilized to test for toxic pesticides- serum psuedocholinesterase activity (SChE).
Toxicology of Therapeutic Drugs
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Analyze the overdose effects of pharmaceutical drugs. Salicylates: Aspirin, analgesic, antipyretic, and anti-inflammatory drug. Functions by decreasing throboxane and prostaglandins formation through inhibition of cycloxygenase. Other effects: interfere with platelet aggregation, gastrointestinal function, relationship with viral infections in children and the onset of Reye’s syndrome.
Various bodily effects: • Because aspirin is an acid leads to metabolic acidosis. • Direct stimulator of the respiratory center and leads to respiratory alkalosis. • Inhibits Krebs cycle leading to excessive conversion of pyruvate to lactate. • Stimulates the use of free fatty acids resulting in ketone body formation. • Treatment: neutralizing and eliminate the excess acid and maintain electrolyte balance.
Assay methods
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? ?
Gas or liquid chromotography-highest analytical sensitivity and specificity. Immunoassay Chromogenic method most common methodtrinder reaction (reacts with ferric nitrate to form a colored complex that can measured by spectrophotmetry.
Acetaminophen
? ? ? ? ?
Analgesic Overdose effects are related to hepatotoxcity High affinity to various proteins, resulting in a low free fraction. Renal filtration in minimal Follows several pathways during the breakdown in the body. The major pathway of concern is the hepatic mixed-function oxidase system. Acetaminophen is transformed to reactive intermediates which conjugate with reduced glutathione, this becomes depleted . Results in accumulation of reactive intermediates inside the cells can form free radicals that can lead to necrosis of the liver.
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In the average adult damage is not seen until 3-5 days after ingestion. Due to the liver effects related to alcoholism, acetaminophen can be more toxic to these individual. Methods: high-performance liquid chromotography (expensive and technical) Immunoassay is the most common
Toxicology of Drugs of Abuse
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Involves urine screen for a substance by qualitative procedure, only identifies the presence of a drug. (Spot Test) Confirmation: what exact drug and how much is present. Methods: immunoassay, Chromogenic, and chromotograohy. Table 29-4
Amphetamines
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Amphetamine and methamphetamines are therapeutic drugs used for narcolepsy and attention deficit disorder. Stimulants with high abuse potential. Produce an initial sense of increased mental and physical capacity along with a perception of wellbeing followed by restlessness, irritability and possibly psychosis. Many OTC drugs contain chemically related amphetamines. (psuedoephenephrine, ephedrine, phenylpropanolamine, etc.) Identification of the drug usually through urine to identify the parent drug.
Anabolic Steroid
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Chemical compound that is chemically related to male sex hormone testosterone. Used to increase muscle mass and enhance performance. Various physical effects including toxic hepatitis with chronic use, enlarge heart, atherosclerosis.
Cannabinoids
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Group of psychoactive compound found in marijuana. Tetrahydrocannabinol (THC) is the most potent and abundant. Produces various physical and metal effects such as impairment of short-term memory and intellectual function. Major urinary metabolite: 11-nortetrahydrocannabinol-9-carboxylic acid (THCCOOH), detected 3-5 days after single use or up to 4 weeks in chronic use. Immunoassay and Gas chromatography
Cocaine
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Effective local anesthetic at therapeutic concentration. High levels it is a potent CNS stimulator. Alkaloid salt that can be administered by insufflation or IV and /or inhaled in free base form. Primary product of hepatic metabolism is benzoylecgonine in urine. (4-7 hrs after use) and detected up to 3 days after single use and 20 days in chronic use. Confirmation test is done by gas chromotograhy.
Opiates
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?
?
Capable of analgesic, sedation and anesthesia Derived from opium poppy, naturally occurring substances include opium, morphine, and codeine. Heroin, hydromorphone, and oxycodone are common substances. High abuse potential. Acute overdose present with respiratory acidosis due to depression of respiratory center and cardiac damage. Initial detection immunoassay.
Phencylidine (PCP)
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?
?
? ?
Illicit drug with stimulant, depressant, anesthetic and hallucinogenic properties. Overdose associated with stupor and coma. PCP is ingested or inhaled by smoking, rapidly distributed into fat and brain. Elimination is slow as a result of redistribution into circulation and hepatic metabolism. Chronic use detected 7-30 days after abstinence Immunoassay is screening procedure.
Sedative Hypnotics
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? ?
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Many therapeutic drugs can be classified as sedative hypnotics or tranquilizers. CNS depressants Valium, Librium, Ativan are common abused benzodiazepines. Immunoassay is most common screening procedure for hypnotics.
doc_241549984.ppt
The presentation describes TDM or Therapeutic Drug Monitoring by analysing topics like purpose, Pharmacokinetic Considerations, Methodological Difficulties.
Therapeutic Drug monitoring
Therapeutic drug monitoring
?
?
?
?
Involves the analysis, assessment and evaluation of circulating concentrations of drugs in serum, plasma, or whole blood. Purpose is to ensure the medication dose is at therapeutic range and not toxic. Medications dosage differ between each patient based on metabolic process. Therapeutic range is narrow for most drugs( below range drug not effective, above rang : drug toxic)
Biological effect
?
? 1. 2. 3.
4.
A drug is effective when it binds to a specific receptor in the target tissue. TDM assumes that serum levels are proportional to the intercellular tissue bind capacity of the drug. Drug utilization in the body is influenced by: Absorption Distribution Metabolism Excretion
Absorption
3 routes of administration for drugs to go through absorption. 1. Orally 2. Rectally 3. IV/IM Orally: drug is absorbed by the GI tract- the drugs are formulated to withstand acid pH in the stomach so that the medication can be absorbed in the intestine.
?
Rectally: drug is absorbed within the And the lining of the lower intestine.
?
IV/IM: the drug is directly administered into the venous flow and absorbed into the tissue. Distribution of Drug: Once in the circulation most drugs are quickly distributed based on the solubility of the drug. Water-soluble vs. water insoluble (need protein carriers: albumin and Alpha1-scid glycoprotein.)
?
?
Theoretically: volume of body fluid needed to dissolve the total amount of drug required to achieve concentration found in the blood. Metabolism: drugs absorbed, distributed and excreted in urine or waste product. The liver metabolized the lipid insoluble drugs into more H2O soluble form. Enzymes in heptocytes help in the conversion of soluble gluconoride, sulfate and phosphate.
excretion
? ?
?
?
Kidneys are the primary excretory organ. Renal disease: other excretory organs or pathway become involved such as: biliary tract, lungs and sweat glands. H2O soluble drugs excrete faster that insoluble. pH of urine is based on the acidic or basic nature of the drug.
Pharmokinectics
?
?
1.
2.
3. 4.
Mathematical model to predict plasma drug levels or their metabolites over a fixed period of time and dosage effects with the least toxic effect. Must consider: Drug elimination from the body is constant. Serum concentration is the same as drug effect. Body is considered a single compartment Distribution is uniform.
?
?
?
?
Process that assist in establishing and modifying a dose regimen. Dose response curve: single dose of medication taken by mouth, the drug response is based on it’s half-life (how long it takes to break down or be metabolized). Trough and Peak levels used to maintain levels. Half-life: time required for drug concentration to be reduced by half. If half life is long: patients metabolize and excreted drug slowly. If half life is short: patients metabolize and excretes drug quickly.
Total body clearance (TBC): 1. Predicts effective dosage 2. Rate of elimination of drug 3. Used to adjust dose and rate of medication. Drug effects: drugs are only effective if at therapeutic levels. Effective when it binds to a specific receptor or target tissue. TDM assumes levels are proportional to intracellular tissue binding to the drug.
?
Factors that effect serum drug levels
Patient compliance 2. Drug absorption 3. Protein binding 4. Enzyme induction Drug disposition: the characteristic of the drug effect how effective the drug is. Factors that affect the effectiveness of medications: Age, Pregnancy, diseases, and the drug itself.
1.
Age
? ?
?
?
Neonates vs. children vs. elderly Neonates: underdeveloped organs (liver/kidneys) and are not able to eliminate drugs as readily. Have to administer decreased doses. Children: (6-10), doses are doubled the adult dose, due to growth process and increased metabolism. Elderly: decrease in proteins, metabolism and renal function therefore easily reach toxic levels, have to decrease dose.
?
? 1. 2. 3.
Pregnancy: hormonal changes, GI emptying, increase body volume and protein concentration change all influence the way the drug is metabolized normally. Disease: Liver: decreases ability to metabolize and excrete. Cardiac: effects blood flow to the GI tract. Renal : problem with elimination and metabolism of drug.
Cardiac medication
? 1. •
• • •
Medication that is used to treat various heart diseases. Digoxin: cardiac glycoside used for CHF. Function by inhibiting membrane Na, K, ATPase. Cause increase calcium levels which improves cardiac contraction. Toxicity affects many organs and cell types. (nausea, vomiting, and visual problems) Absorption orally is variable and is influenced by dietary factors and formulation of the drug Elimination occurs by renal filtration
? 1.
2.
3.
Digoxin Serum levels are influenced by glomerulus filtrate rate. Concentration of electrolytes. (low K and Mg potentiate digoxin levels) Thyroid status (Hyper: resistant, Hypo: more sensitive)
Lidocaine
?
?
Used to correct ventricular arrhythmias and prevent ventricular fibrillation. Completely eliminated by the liver If orally given as monoethylglycinexylidide (MEGX).
Quinidine
?
? ?
?
Used to treat cardiac arrhythmic disorders in the form of quinidine sulfate fast half-life) and quinindine gluconate (slow half-life) Liver disease may extend half-life. Toxic effects see nausea, vomiting, and abdominal discomfort Eliminated by the liver.
Procainamide
? ?
?
? ?
?
Treats arrhythmic disease Absorbed by GI tract rapidly Eliminated by renal filtration and hepatic system. Major metabolite: N-acetylprocainamide (similar to procainamide) Increased concentration due to over dose or lack of elimination results in myocardial depression and arrhythmia. Assay: must differentiate the porcainamide from Nacetyl-procainamide.
Disopyramide
? ?
?
Used as a quinidine substitute Eliminated by renal filtration and some hepatic Toxicity symptoms: dry mouth and constipation.
Antibiotics
?
?
?
?
Aminoglycosides: treat infection with gram negative bacteria. Gentamycin, tobramycin, amikacin, and kanamycin Toxicity involve; nephrotoxicity and ototoxcity (ear) and effects balance and hearing. Eliminated by renal system
Vancomycin
?
? ?
?
Glycopeptides: effective against Gram positive cocci and bacilli. Poor oral absorption, given IV. Toxicity: kidney, ototoxicity, Red-man syndrome( flushing of skin of the extremities) Eliminated by renal excretion
Antiepileptic drugs
Used to treat epilepsy, seizures and convulsions on a prophylactic bases. ? Phenobarbital: is a barbiturate that is absorb slow orally and has a long half-life. ? Primidone is its proform (inactive)- rapidly absorbed and converted into the active form.
?
? ?
?
Phenytoin (dilantin): used to treat seizure disorders and brain injury to prevent loss of functional tissue. Unbound form is the active form. Adverse effects: hirsutism, gingival hyperplasia, vitamin D, and folate def. Eliminated by hepatic metabolic process
Valporic Acid
? ? ? ? ?
Used petit mal and absence seizure. GI absorption is rapid and complete. Circulates protein bound (93%). Eliminated by hepatic system Nausea, lethargy and weight gain are most common adverse effect.
Carbamazepine
Used to treat various seizure disorders. ? Can cause serious toxic adverse effects ? Circulates protein bound (70-80 %) ? Eliminated primarily by hepatic metabolism. ? Any liver dysfunction can results in serum accumulation. Ethosuximide: used to control petit mal seizure, admin.
?
Psychoactive Drugs
?
Lithium: Used to treat manic-depression (bipolar disorder). Absorption is complete and rapid. Distribution is uniform throughout the body. Eliminated by renal function. Concentration levels 1.2-2 mmol/l cause apathy, lethargy, speech difficulty's and muscle weakness. Concentrations greater than 2.0 mmol/L may cause muscle rigidity, seizures and coma.
?
Tricyclic antidepressants (TCS) used to treat depression, insomia, extreme apathy and loss of libido. Examples: imipramine, aminitriptyline, and doxepin. All have a variable degree of absorption. Circulate protein bound (85-95%). Therapeutic levels may take as longs as 2-4 weeks. Toxicity may cause drowsiness, constipation, blurred vision and memory loss.
Bronchodilators
?
Theophyline: used to treat asthma and chronic obstructive pulmonary diseases. Used in acute and prophylactic treatment. Absorb form circulates protein bound (50%). Eliminated by both renal and hepatic organs. Therapeutic range is narrow, toxicity include nausea, vomiting and diarrhea.
Immunosuppressive drugs
?
?
?
Used to prevent rejection in various organ transplantation procedures. Cyclosporin: cyclic polypeptide used to prevent GVHD or heterotrophic transplant organs. Tacrolimus: 100X more potent than cyclosporine, used in same manner just takes less medication.
Antineoplastics
? ?
Used to treat neoplastic disorders (cancer) Methotrexate: inhibits DNA synthesis in all cells.
Chapter 29 Toxicology
? ?
1.
2.
3. 4.
Stud of poisons. Four disciplines: Mechanistic: basis for rational therapy design and the development of tests. Descriptive: result of animal test to predict harmful effects to humans. Forensic Clinical diagnostics: diagnosis of interrelationships of toxins and disease states.
Exposure to toxins
? ? ? ?
Occurs by various routes: Suicide (50%) Accidental (30%) Rest are related to occupational exposure or homicide
Routes of exposure
? ? ?
Ingestion Inhalation Transdermal absorption
Dose-response relationship
?
? ?
?
Poison: any substance that causes a harmful effect upon exposure. Dose is a key issue. There are various toxic effects from drugs based on dose including death. Dose-response implies that there will be an increase in the toxic response as the dose is increased.
?
Acute toxicity: associated with a single, short term effect to a substance, the dose is sufficient to cause immediate toxic effect.
Chronic toxicity: associated with repeated exposure for extended periods, at a dose that are insufficient to cause immediate acute response.
?
Analysis of toxic agents
Two-step procedure Screening test, which is a rapid , simple analysis that is qualitative procedure to detect specific classes or substance. Lack specificity. Tells us something is there just not specific to what. Confirmatory test: test utilizing more specificity- tells us what drug and how much. Methods: gas chromatography using mass spectrophotometer.
Specific agents
?
?
Alcohol: common depressant of the central nervous system. Perform Blood alcoholsalong with liver panel to evaluate toxicity. Methanol: common solvent ingested accidentally or from contaminant of homemade liquors. Death can occur due to the formation of formic acid leading to severe acidosis.
Isopropanol: rubbing alcohol, by product acetone. Both are CNS depressants ? Ethylene glycol: common component of anti-freeze. Causes crystallization of calcium oxalate within the renal system and cause tubular damage if dosage high. Determination: serum, plasma, whole blood used in correlation with psychomotor test for alcohol, do not use alcohol to clean area for venipuncture can contaminate. Analytical method enzymatic gas chromatography.
?
?
?
?
?
Carbon monoxide: by product of incomplete combustion of carbon containing substances (gasoline engines, furnaces and wood or plastic fires.) Colorless, odorless and tasteless gas that is absorbed into the blood from inhaled air. Toxic effect is due to its affinity for divalent iron within heme (hgb, myoglobulin, etc). Hgb affinity has the most effect due to the production of carboxyhemoglobulin (245X greater affinity)
O2 and CO2 compete for the binding sites on the RBC, decrease O2 carrying capacity in the presence of CO2. ? Methods: 1. Spot test: using 5 ml of 40% NaOH mixed with 1/20 aqueous dilution of whole blood yielding a pink color if CO2 present at 20% or greater value ( CO2 produces a cherry red color compound) 2. Quantitative method (differential spectrophotometry and gas chromotography) Causative agent: occupational or household exposure of cleaning agents.
?
Cyanide
?
?
?
?
?
Supertoxic substance that exist as a gas, solid or in solution. Exposure can occur through inhalation, ingestion, or transdermal absorption. Found in insecticides and rodenticides Toxic effect involves its ability to bind heme iron. Method for analysis: Ion specific electrode and photometric.
Metals
Arsenic: exist bound or as primary constitute of organic and inorganic compounds. • Found naturally and can be manmade forms. • Exposure through environment occurs around industries. • Absorption of arsenic depends on the form. • Toxicity related to the binding ability to protein. • Assay: atomic absorption spectrophotometry.
Cadium
?
? ? ?
Metal found in industrial processes (electroplating and galvanizing) Pigment found in paints and plastics. Significant environmental pollutant. Exposure occurs through inhalation, toxicity related to ability to bind to protein tends to accumulate in the kidney’s.
Lead
? ? ? ?
?
?
Common environmental contaminant Use to be used in household paint and gasoline. Exposure can occur in various route- most is through dietary ingestion of contaminated material. Toxicity related to ability to bind to macromolecular structures. Distributes into the bones and soft tissue in theory. Elimination occurs through the renal system. Lead toxicity has various physical effects (neurological, ADHD, ADD, decreased intelligence. Potent inhibitor of many enzymes (Vit. D, heme synthetic pathway) resulting in bone and calcium metabolism and in anemia.
?
?
Treatment involves using a therapeutic chelater such as EDTA and DMSA. Assay: chromogenic reaction and anodic stripping voltametry methods. Most common method AAS.
Mercury
? ? ?
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Metal found in three forms: elemental, inorganic salts or organic compound. Exposure occurs through inhalation and ingestion (contaminated food) Each form vary in toxic effect. (organic is the most toxic) Toxicity related to ability to bind protein resulting in a change of structure and function. Inhibits a number of enzyme activities. Many biological effect most noted is renal. Assay: AAS
Pesticides
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Substance that are intentional used to kill or harm an undesirable life form. Categorized as insecticide and herbicides which are used to control of vector-borne disease and urban pest and to improve agricultural productivity. Contamination of food is the major route of exposure. Inhalation, transdermal absorption and ingestion through hand-to mouth contact are common occupational and accidental exposure.
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Actions of most are nonselective and result in toxic effect to various organs. Wide variation of pesticides that range from salts to heavy metals. Organophosphate and carvamates function by inhibition of acetylcholine esterase. Acetylcholine is a neurotransmitter and has many effects in the body. Test utilized to test for toxic pesticides- serum psuedocholinesterase activity (SChE).
Toxicology of Therapeutic Drugs
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Analyze the overdose effects of pharmaceutical drugs. Salicylates: Aspirin, analgesic, antipyretic, and anti-inflammatory drug. Functions by decreasing throboxane and prostaglandins formation through inhibition of cycloxygenase. Other effects: interfere with platelet aggregation, gastrointestinal function, relationship with viral infections in children and the onset of Reye’s syndrome.
Various bodily effects: • Because aspirin is an acid leads to metabolic acidosis. • Direct stimulator of the respiratory center and leads to respiratory alkalosis. • Inhibits Krebs cycle leading to excessive conversion of pyruvate to lactate. • Stimulates the use of free fatty acids resulting in ketone body formation. • Treatment: neutralizing and eliminate the excess acid and maintain electrolyte balance.
Assay methods
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Gas or liquid chromotography-highest analytical sensitivity and specificity. Immunoassay Chromogenic method most common methodtrinder reaction (reacts with ferric nitrate to form a colored complex that can measured by spectrophotmetry.
Acetaminophen
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Analgesic Overdose effects are related to hepatotoxcity High affinity to various proteins, resulting in a low free fraction. Renal filtration in minimal Follows several pathways during the breakdown in the body. The major pathway of concern is the hepatic mixed-function oxidase system. Acetaminophen is transformed to reactive intermediates which conjugate with reduced glutathione, this becomes depleted . Results in accumulation of reactive intermediates inside the cells can form free radicals that can lead to necrosis of the liver.
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In the average adult damage is not seen until 3-5 days after ingestion. Due to the liver effects related to alcoholism, acetaminophen can be more toxic to these individual. Methods: high-performance liquid chromotography (expensive and technical) Immunoassay is the most common
Toxicology of Drugs of Abuse
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Involves urine screen for a substance by qualitative procedure, only identifies the presence of a drug. (Spot Test) Confirmation: what exact drug and how much is present. Methods: immunoassay, Chromogenic, and chromotograohy. Table 29-4
Amphetamines
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Amphetamine and methamphetamines are therapeutic drugs used for narcolepsy and attention deficit disorder. Stimulants with high abuse potential. Produce an initial sense of increased mental and physical capacity along with a perception of wellbeing followed by restlessness, irritability and possibly psychosis. Many OTC drugs contain chemically related amphetamines. (psuedoephenephrine, ephedrine, phenylpropanolamine, etc.) Identification of the drug usually through urine to identify the parent drug.
Anabolic Steroid
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Chemical compound that is chemically related to male sex hormone testosterone. Used to increase muscle mass and enhance performance. Various physical effects including toxic hepatitis with chronic use, enlarge heart, atherosclerosis.
Cannabinoids
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Group of psychoactive compound found in marijuana. Tetrahydrocannabinol (THC) is the most potent and abundant. Produces various physical and metal effects such as impairment of short-term memory and intellectual function. Major urinary metabolite: 11-nortetrahydrocannabinol-9-carboxylic acid (THCCOOH), detected 3-5 days after single use or up to 4 weeks in chronic use. Immunoassay and Gas chromatography
Cocaine
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Effective local anesthetic at therapeutic concentration. High levels it is a potent CNS stimulator. Alkaloid salt that can be administered by insufflation or IV and /or inhaled in free base form. Primary product of hepatic metabolism is benzoylecgonine in urine. (4-7 hrs after use) and detected up to 3 days after single use and 20 days in chronic use. Confirmation test is done by gas chromotograhy.
Opiates
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Capable of analgesic, sedation and anesthesia Derived from opium poppy, naturally occurring substances include opium, morphine, and codeine. Heroin, hydromorphone, and oxycodone are common substances. High abuse potential. Acute overdose present with respiratory acidosis due to depression of respiratory center and cardiac damage. Initial detection immunoassay.
Phencylidine (PCP)
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Illicit drug with stimulant, depressant, anesthetic and hallucinogenic properties. Overdose associated with stupor and coma. PCP is ingested or inhaled by smoking, rapidly distributed into fat and brain. Elimination is slow as a result of redistribution into circulation and hepatic metabolism. Chronic use detected 7-30 days after abstinence Immunoassay is screening procedure.
Sedative Hypnotics
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Many therapeutic drugs can be classified as sedative hypnotics or tranquilizers. CNS depressants Valium, Librium, Ativan are common abused benzodiazepines. Immunoassay is most common screening procedure for hypnotics.
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