Exam 2: Lecture 27 Flashcards
(51 cards)
1
Q
Toxicology
A
is the study of harmful effects of chemicals on biological systems
2
Q
Poison
A
is any substance that can cause death, disease, or injury
3
Q
What are the routes of exposure?
A
- oral, parenteral, or dermal
4
Q
How are poisons classified by their broad headings?
A
- corrosive
- irritants
- systemics
- gases
5
Q
How are poisons classified by their chemical structures?
A
- acids
- bases
- organic solvents
- heavy metals
6
Q
What dictates the effect of poison in association with length of time?
A
- dose
- age
- personal habits
- genetics
7
Q
Toxicokinetics
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-ADME of toxins, toxic doses of therapeutic agents, and their metabolites
8
Q
Toxicodynamics
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the injurous effects of these substances on vital functions
9
Q
LD50
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Dose of a chemical required to produe death in 50% of teh organisms that is exposed to it
10
Q
ED50
A
dose producing the desired pharmacological effect in 50% of the individuals
11
Q
TI (Therapeutic index)
A
- LD50/ED50
- The larger the number is, the safer the drug is
12
Q
What are teh route sof exposure?
A
GI
lungs
skin
parenteral (IV)
13
Q
Duration of exposure
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- acute exposure: a single exposure or multiple exposures over 24 hr period
- subacute: multiple exposures over 24 hrs- 3 months
- Chronic exposure: multiple exposures over a period of 3 months or more
14
Q
Cumulative vs non- cumulative
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Cumulative: irreversible effects even with low doses; metabolize at low rates with a relatively long half-life–>Cd and genotoxic carcinogens
- produces reversible effects at low doses; total dose over time is not as critical; metabolism and excretion —> ex. acetaminophen and ethanol
15
Q
Drug elimination: Therapeutic conditions vs overdose or poisoning
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- therapeutic conditions: first order process
overdose or poisoning: zero order
16
Q
Zero kinetics vs first order kinetics
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- first order depends on some fraction
- zero order- set constant amount per hour
17
Q
A
- less toxic/ less potent in its toxicity because its LD50 is higher
18
Q
Margin of safety
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- separation between ED curve and LD curve
- small changes of dose and a larger margin of safety, you wouldnt exhibit adverse effects
- if margin of safety os sammler, you poternially could
19
Q
Safer drugs have higher TI
A
20
Q
What is the difference between hypersensitive and hyposensitive?
A
- hypersensitive: a given response occurs at a lower dose
- hyposensitive: a given response occurs at a higher dose
21
Q
Describe the 4 dose-response patterns
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1) Threshold–> no response below a certain dose, then linear increase in toxic response with dose
2) Hormetic –> Beneficial response at low doses, then transition to toxic response with increasing dose
3) Linear (no threshold) –> increasing toxic response with dose
4) Supralinear–> increasing toxic response with dose; nonlinear increase with dose
22
Q
Name heavy metals taht are not metabolized
A
- Lead
- mercury
- arsenic
- cadmium
23
Q
Lead poisoning: Acute
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- severe GI distress and progresses to CNS abnormalities
- difficult diagnosis ; symptoms similar to appendicitis, peptic ulcer, and pancreatitis
24
Q
Lead poisoning: Chronic
A
- symptoms: weakness, anorexia, nervousness, tremor, weight loss, headache, GI distress
- Recurrent abdominal pain and extensor muscle weakness without sensory disturbances
- confirm diagnosis via meadure blood lead, identifcation of porphyrin metabolism
25
What is the pharmocokinetics of lead?
- following absorption--> distributed to soft tissue, primarily kidneys and liver
- eventually distributed and deposited in bones, teeth, and hair
- eventually, 95% of body lead burden in bones
- most circulating inorganic lead is associated with RBC
half-life in blood is 1-2 months and in bone is 20 yrs
- excretion in urine and feces
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What are the diagnoses of lead poisoning?
- easily missed
- primary screening procedure: free erythrocyte protoporphin (FEP) TEST...FEP over 1.1mg/mL is indicative of lead intoxication
- Erythrocyte protoporphyrin increases due to inhibition of ferrochelatase
- lead inhibits delta aminolevulinate dehydratase
- patient with lead poisoning have urine lead concentrations of 150-300 mu grams/L
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What are the biochemical effects of lead?
- inhibition of several SH- containing enzymes in heme biosynthesis
- causes elevated urinary d-ALA, coproporphrin, and porphrin
- causes anemia by inhibiting Hb synthesis in bone marrow and increasing fragility of RBC [hypochromic (low color) and microcytic (small size)]
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How does lead inhibit heme biosynthesis?
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How do treat lead poisoning?
- prevent further exposure and give supportive measures
- treat seizures with diazepam
- treat cerebral edema with mannitol and dexamethasone
- critical to maintain fluid and electrolyte balance
- initiate chelation therapy as soon as possible
30
Name some chelators often used to treat lead poisoning
- Dimercaprol
- Edetate calcium disodium (CaNa2EDTA)
-D-Penicillamine
- Dimercaprol and CaNa2EDTA usually in combo follow by oral penicillamine, which is used for long term treatment
31
What are the forms of mercury?
- elemental mercury- a liquid
- inorganic mercury salts
- organic mercurials
- basic properties: high toxic, silver-white liquid metal, slightly volatile at room temp
- inhaled mercury is primary form of occupational exposure
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Describe pharmacokinetics of mercury
- absorption varies with chemical form of the metal
-organic mercurials are absorbed through the GI tract than inorganic forms
- after absorption, mercury distributes to tissues within a few hours, with highest concentrations in renal proximal tubules
- mercury readily binds to SH groups
- excretion through urine
- inorganic mercury in body excreted over a 1-week period, but kidneys and brain retain mercury for longer periods
- short chain organic mercurials are predominately distributed to CNS
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Describe acute mercury intoxication
- occurs from inhalation of mercury vapor
- symptoms: chest pains, shortness of breath, metallic taste, nausea, vomiting
- acute damage to kidneys occurs next
- if patient survives, severe gingivitis and gastroenteritis occurs on the 3rd or fourth days
- in most severe cases, severe muscle tremor and psychopathology develop
34
Describe chronic mercury intoxication
- complaints of mouth and GI disorders; signs of renal insufficiency may be present
- gingivitis, discolored gums, loose teeth common
- salivary glands may be enlarged
- tremor involving fingers, arms, and legs often present
- altered handwriting frequently observed
- ocular changes, including deposition of mercury in the lens
- hair analysis of mercury may be useful for diagnosis
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What are the biochemical effects of mercury?
- mercuric ion readily forms covalent bonds with SH group of intracellular proteins; accounts for most of toxicity
- very corrosive due to its ability to precipitate protein on contact
- even in very low concentrations, mercurials are capable of inactivating SH enzymes and interfering with cellular metabolism and function
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How do you treat Hg poisoning?
- Acute? Chronic?
- acute: removal from exposure and chelation treatment with dimercaprol (3-5 mg/kg i.m. every 4 hr for 48 hr and then every 12 hr for 10 days); if renal damage occurs, hemodialysis is required
- Chronic: oral penicillamine or N-acetylpenicillamine (250-500 mg orally 4x/day for 10 days); 2,3- dimercaptosuccinic acid (DMSA) may be useful
- monitor urinary Hg levels to assess removal of Hg by chelators
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What are the chemical forms of arsenic? What profession exposure do you typically receive?
- employees of coal-burning power plants and ore smelters may have exposure to arsenic; contaminant of water supply
- Chemical forms: elemental arsenic, inorganic arsenic, organic arsenic, arsine gas
- use arsenic for tropical diseases
- arsenic in herbicides, insecticides, fungicides, algicides, and wood preservatives
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Describe the toxicology of arsenic
- major toxic effects of inorganic As due to trivalent arsenic (As+3)
- As+3 acts as a sulfhydryl reagent, inhibiting SH-sensitive enzymes
-Pyruvate dehydrogenase (PDH) systems very sensitive; the 2 SH-groups of lipoic acid readily react with As+3 to form a stable, 6 membered ring
- pentavalent arsenic (As+5): well known uncoupler of mito oxidative phosphorylation; competes with inorganic phosphate in the formation of ATP
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How do you treat arsenic poisoning?
- first, stabilize the patient and prevent further absorption
- chelation therapy with dimercaprol; may then follow with penicillamine
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Describe Cadmium (Cd)
- cigarette smoke contributes to cadmium intake
- Cd half-life in the body is 10 -30 years
- tissue concentrations of cadmium increase throughout life with continuous environmental exposure
- Cd is an environmental poison that is prone to accumulation
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How do you treat cadmium?
- initial treatment involves patient stabilization and prevention of further absorption of cadmium
- chelation therapy with edetate calcium disodium recommended, but is of questionable utility
- treatment with dimercaprol is contraindicated because it mobilizes the cadmium and causes it to concentrate further within kidneys, where it dissociates from the chelator, thereby producing increased nephrotoxicity
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What are heavy metal antagonists or chelating agents?
- binds these metals and either prevent or reverse the binding of the metals to cellular molecules
- chelators are usually flexible molecules with 2 or more electronegative groups that can form stable coordinate-covalent bonds with the cationic metal atom
- binding happens with sharing pairs of electrons between the metal ion and the ligand. Generally, both electrons of the shared pair are supplied by the ligand
- the most common donor atoms that supply the electrons are the nitrogen, sulfur, and oxygen
- chelation complexes are the excreted by the body
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What dictates the effectiveness of chelating agents for treating heavy metal poisoning?
- affinity of the chelator for the heavy metal vs its affinity for essential metals in the body
- distribution of chelator in body vs distribution of metal
- ability of the chelator, once it has bound to the metal, to mobilize it from the body
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What 7 properties should be exhibited by a chelating agent?
1) good water solubility
2) resistance to metabolism in vivo
3) ability to get to site where the metal ions have sequestered
4) ready excretion of the chelate
5) ability to chelate the toxic agent at pH of body fluids
6) complexes formed with metals should be less toxic than the free metal ions
7) greater affinity of the chelating agent for the metal than that possessed by endogenous ligands
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What are the potential pitfalls of chelators?
- Some chelators are nonspecific and may chelate essential metals such as calcium, zinc, and magnesium
- Thus, low affinity for calcium and zinc is also a desirable property
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Chelating Agent: Dimercaprol (BAL)
- useful antidote for As, Pb, and Hg, but NOT Cd
- when given i.m., readily absorbed, metabolized, and excreted by kidneys within 4 hr
- contraindicated in presence of liver disease or severe renal disease
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What are the adverse effects of Dimercaprol (BAL)
- cardiovascular (hypertension, tachycardia), headache, nausea, vomiting
- congeners that are more soluble with less side effects: 2,3-dimercaptosuccinate (DMSA); 2,3- dimercaptopropane-1-sulfonate (DMPS)
-
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Edetate Calcium Disodium (CaNa2EDTA)
- ethylenediaminetetraacetate (EDTA) is a efficient chelator of many divalent and trivalent metals
- EDTA penetrates cell membranes relatively poor, so it serves primarily as an extracellular rather than an intracellular chelator
- Calcium is readily displaced from the chelation complex by lead, zinc, chromium, copper, cadmium, manganese, and nickle --> can be used in treatment of poisoning by these heavy metals
- SHOULD NOT be used for the mobilization of Hg
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Penicillamine
- formed by the degradation of penicillin
- D- isomer is less toxic than the L isomer
- Penicillamine and its acetyl derivative, N acetylpenicillamine, can chelate copper, iron, lead, mercury, and other metals.
- used in the treatment of Wilson's disease (hepatic degeneration due to copper excess)
- acute use is fine; chronic use is associated with acute allergic reactions, leukopenia, eosinophilia, and nephrotoxicity
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Deferoxamine mesylate
- binds iron , but has a low affinity for trace metals or for calcium
- it will remove iron from some cellular proteins, but not from Hb or cyto
- chelator of choice for iron poisoning
- maybe useful in the treatment of aluminum toxicity
- excrete almost entirely in urine, so renal insufficiency is a contraindication
- adverse reactions: diarrhea, hypertension, cataract formation
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