Lecture 4 And 5, Core Ii Toxic Agents And Pesticides

Front 1

What are the four sources of Carbon Monoxide?

Back 1

1. Inadequate venting of furnaces and automobiles
2. Fires
3. Smoking Cigarettes
4. it is a byproduct of incomplete combustion of
organic matter
4.

Front 2

What is the mechanism for Carbon Monoxide and the body?

Back 2

Carbon Monoxide (CO) binds to the oxygen binding site on hemoglobin. CO has an affinity 220 x greater than oxygen for hemoglobin, and thus reduces the uptake of O2.

Front 3

What is a carboxyhemoglobin?

Back 3

Carbon Monoxide that is bound to a Hemoglobin molecule.

Front 4

CO decreases the amount of O2 for body in two ways:?

Back 4

1. It competes for binding to hemoglobin. (220x higher affinity); less transport of O2.
2. It decreases the ability of Hemoglobin to release O2 for the tissues. Decreases delivery of O2 to tissues.

Front 5

Describe the cooperative binding of Hemoglobin to Oxygen?

Back 5

Hemoglobin has four subunits and each subunit has one heme that binds an Oxygen molecule. After the binding of one O2 molecule, the next one has a higher affinity.
Conversely, after the dissociation of one O2 at the tissue, the other subunits dissociate easier.

Front 6

Why is the oxygen dissociation curve sigmoidal?

Back 6

To ensure maximum uptake of O2 at the level of the lung and maximum delivery at the level of the tissue.

Front 7

Presence of CO affects the Oxygen dissociation curve in two ways:?

Back 7

1. Changes from sigmoidal to hyperbolic
2. Decreases the dissociation of Hb-O2 at tissue pO2.

Front 8

What are the two organs most affected by low levels of O2?

Back 8

brain and heart (use the most)

Front 9

Symptoms of Hypoxia include: (in sequence)

Back 9

1. Headache, tightness in temporal area, confusion, loss of visual acuity
2. Tachycardia, coma, convulsions, respiratory failure
3.

Front 10

A measure of what molecule correlates with the severity of poisoning of CO?

Back 10

carboxyhemoglobin.

Front 11

Who is more susceptible to the dangers of CO? (name about 5 categories)

Back 11

1. Individuals with CVD are more vulnerable to CO because of their inability to compensate for hypoxia.
2. Anemic persons already have low oxygen levels and are more likely to feel the danger.
3. Children, compared to adults, succumb earlier due to their high metabolic rates.
4. Pregnancy: the fetus is very sensitive as CO can pass through the placenta and the fetal hemoglobins ability to deliver O2 is already low (Curve lies to the left of adults)
5.High Altitudes: because pO2 levels are lower, and CO would have greater affect.

Front 12

What are some possible treatments for CO poisoning/hypoxia?

Back 12

1. Increasing dissolved oxygen in the blood to better compete with CO to hemoglobin. With a higher % of O2 available, the half timeof CO is reduced
2. 100% oxygen is administered to CO poisoned patients
3. Hyperbaric Therapy: beneficial for severely poisoned patients. (carboxy levels greater than 25%)

Front 13

What are some sources of Cyanide poisoning? (A solvent)

Back 13

1. Household: found in plant seeds, silver polish, insecticides, rodenticides
2. Combustion: nitrogen containing plastics (polyurethane) releas cyanide
3. Drug Therapy: cyanide is a metabolite of nitroprusside, a vasodilator used for hypertension

Front 14

WHat is the molecular mechanism for cyanide?

Back 14

Cyanide binds to the ferric iron of cytochrome oxidase and stops the electron transport chain in the mitochondria. --> Cellular respiration is thus inhibited and oxygen utilization is blocked. Death is due to respiratory failure.

Front 15

What are the clinical presentations of cyanide poisoning?

Back 15

1. Signs and symptoms of cellular hypoxia
2.Bright red venous blood
3. Bitter almond breath
4 Rapid onset of coma

Front 16

HOw is cyanide poisoning treated? What are the three steps?

Back 16

By reversing the bond to cytochrome oxidase
Step 1: Administer amyl nitrite to oxidate hemoglobin to methemoglobin. Methemoglobin competes with cytochrome oxidase for Cyanide, and forms cyanomethemoglobin.
Step 2: Administer sodium thiosulfate which binds to CN as it dissociates from cyanomethemoglobin. THis makes thiocyanate. THis is much less toxic and is excreted by the kidneys
Step 3: Administer methylene blue to reduce methemoglobin back to hemoglobin.

Front 17

What are some sources of methanol poisoning? (solvent)

Back 17

antifreeze, windsheilf washer fluid, paint removers, alcohol

Front 18

Methanol poisoning is Often seen in whom?

Back 18

Chronic Alcoholics who abuse denatured alcohol in which methanol is used as an adulterant.

Front 19

What is the mechanism of action of methanol

Back 19

Methanol is very much like ethanol in terms of its effect on the CNS. however, it is metabolized to a toxic compound, formic acid. Formic acid accumulates and it damages retinal cells, causing blindness and severe acidosis (anion gap)

Front 20

What are the clinical presentations of methanol poisoning?

Back 20

Initial: Mild CNS depression
GI Tract: Vomiting, nausea and abdominal pain,
Latent Period 12-24 hours
Ocular Toxicity: blurred vision, photophobia, papilledema"feeling of being in a snowfield"

Front 21

What are some treatments for methanol poisoning?

Back 21

1. Antidote: Administeration of ETHANOL because Ethanol has 10 to 20 x greater affinity for alcohol dehydrogenase, thus slowing down the metabolism of methanol, lowering formic acid productiong
2. Bicarbonate: Administered to correct metabolic acidosis
3. Hemodialysis: enhances the removal of methanol and formic acid
4. Folate: enhances the conversion of formic acid to carbon dioxide

Front 22

Compare the oxygen dissocation curve of a fetus and an adult:

Back 22

Fetus: hyperbolic, shifted to the left (less dissociation of O2 at tissue pO2), higher oxygen desire

Front 23

Why is methanol dangerous?

Back 23

Leads to the production/accumulation of formic acid --> Damages retinal cells, optic nerve damage AND causes severe acidosis

Front 24

What is the primary source of iron poisoning? The most deaths occur in?

Back 24

Pills .
accidental uptake by Children

Front 25

What are symptoms of iron poisoning?

Back 25

1. GI irritation and bleeding
2. mEtabolic acidosis
3. Hepatic Failure
4. Pulmonary edema

Front 26

What are two effects of iron on the GI tract?

Back 26

1. Inhibits blood coagulation
2. Corrosive effect of iron can cause erosion and ulceration

Front 27

What protein stores iron? Where is Iron stored? (What organ)

Back 27

Ferritin. Liver.

Front 28

How does a chelator work as an antidote for Iron?

Back 28

Competes with enzymes, traps metal ions, facilitates rapid elimination.

Front 29

What is deferoxamine?

Back 29

A chelator for iron. High affinity for Iron and removes iron from ferritin

Front 30

What are the risk vs benefits of using deferoxamine (iron chelator)

Back 30

Risk: Diarrhea, hypotension, tachycardia
BEnefit: To prevent..
Hepatic failure
Pulmonary Edema
Death

Front 31

What are the sources of lead poisoning?

Back 31

Lead based paint, lead lined containers, lean-contaminated water soldering and lead industry

Front 32

What does lead do in the body?

Back 32

Lead binds to erythrocytes; first distributes to soft tissue and then to bone!

Front 33

How is diagnosis of lead poisoning made?

Back 33

1. Blood lead levels
2.free erythrocyte protophorphyrin
3. X ray of long bones ( to see lead lines)

Front 34

HOw is lead poisoning treated

Back 34

Chelation Therapy: severe exposure is treated with Calcium disodium EDTA in order to remove lead from bone and dimercaprol to remove lead from tissues.

Front 35

How do chelators work as antidotes?

Back 35

Heavy metals bind to functional groups like -OH, -SH, -NH on proteins and interfere with the activity of enzymes. Chelators, by having similar functional groups, bind heavy metals to prevent worse toxicity. Also, chelator-metal complexes are easily excreted by the kidneys.

Front 36

What are the lead mechanisms leading to toxicity? (3)

Back 36

1. Lead interferes with the action of Ca2+. acts as an antagonist
2. Lead complexes with OH, SH and NH. Especially SH.
3. It inhibits activity of enzymes with sulfylhydryls in the active sites.

Front 37

What are other toxic effects of lead in children?

Back 37

1. Encephalopathy: starts with irriation, continues to seizures and comas
2. Learning problems, lower IQ scores

Front 38

What are other toxic effects of lead in adults?

Back 38

1. Peripheral Neuropathy.
2. Damage to proximal tubules in the kidney and may cause hypertension.

Front 39

What are the primary dangers with lead toxicity?

Back 39

Interference with Ca2+ absorption.
Inhibition of heme synthesis.
Hypochromic Microcytic anemia

Front 40

What is Calcium Disodium EDTA used for? HOw does it work?

Back 40

For lead toxicity. It is used as a Ca2+ chelated complex. Does not chelate Ca2+ from the plasma. Metal ions with higher affinity than Ca2+ will be chelated. Lead displaces Ca2+ from EDTA

Front 41

Whats the problem with using Disodium EDTA as a chelator?

Back 41

It leads to severe hypocalcemia because it steals all the Ca2+ in blood.

Front 42

What is dimercaprol? Its used to treat?
What is succimer?
Which one is more safe?

Back 42

Dimercaprol: A chelator. Chelates metals through sulfylhydrils. Used to treat gold, mercury, arsenic
Succimer: water soluble analog of dimercaprol. More Safe!

Front 43

Who is exposed to Chlorinated Aromatic Hydrocarbons? What can lead to CAH poisoning? Whats an example?

Back 43

INustrial or agricultural workers. Accidents, residues on foods, and the pollution of water can lead to acute or chronic poisoning
"Dioxin"

Front 44

What are some common characteristics of CAH's?

Back 44

Lipophillic compounds -stored in body fat and accumulate in food chains
2. Affect CNS by crossing blood brain barrier
3. Secreted in Milk
4. PErsistant in the environment, they are broken down slowly
5. Cross the placenta; accumulate in placenta and fetus

Front 45

What is the mechanism for CAH?

Back 45

dioxin and other CAH bind to a cystolic protein, arylhydrocarbon receptor. This receptor translocated into the nucleus and activates DNA genes which lead to the production of proteins and Ah hydroxlyase. THis is correlated with toxicity.

Front 46

Acute poisoning of CAH's leads to:

Back 46

1. CNS: stimulation of all parts leading to excitations and convulsions.
2. Cardiac: arrythmias and fibrillation due to sympathetic overactivity
3. liver and kidney damage
4. Chlorane: severe skin eruptions

Front 47

Chronic poisoning of CAH leads to:

Back 47

1.Hepatic Porphyria: accumulation of porphyria.
2. Impaired fertility. (toxic effects on sperm)
3. Toxicogenecity: high for rodents, not clear for humans

Front 48

High level of porphyrins are often seen in urine of those with CAH poisoning. Why is this dangerous?

Back 48

skin lesions, hyperpigmenation, photosensitivity

Front 49

What is cholestyramine used for?

Back 49

Orally administered drug to increase excretion of CAH's. CHolestyramine removes bile salts from the intestine and bile salts normalls facilitate the reabsorption of CAH. It blocks enterohepatic recirculation.

Front 50

What is enterohepatic circulation?

Back 50

When toxins like CAH are secreted from the liver into the gut but then are reabsorbed

Front 51

What is "agent orange"?

Back 51

A toxin used in vietnam war that had various amounts of the toxin DIOXIN. Major symptoms: skin disease, liver, spleen, kidney ailment. Increased incidence of certain birth defects

Front 52

What is paraquat?

Back 52

A pesticide. Bypyridal class of herbicides

Front 53

Dangers of paraquat?

Back 53

Reported to cause accidental or suicidal fatality
2. Damages lung, kidney, liver

Pulmonary fibrosis is usually the cause of death!

Front 54

Mechanism of paraquat

Back 54

Induces the generation of super oxide radicals from oxygen--> induces lipid peroxidation --> damages cell membranes and enzymes --> tissue damage --> Pulmonary Fibrosis -->Eventual delayed death due to respiratory distress

Front 55

Treatment: ?
What should not be given for treatment:?

Back 55

1. REmoval of unabsorbed paraquat by gastric lavage or activated charcoal
2. REmoval of absorbed paraquat by hemodialysis, hemoperfusion, serial activated charcoal
DO NOT TREAT WITH: 100% oxygen. This actually enhances paraquat toxicity

Front 56

What are the three classes of pesticides?

Back 56

1. Chlorinated Aromatic Hydrocarbons (dioxin)
2. Bipyridal class of herbicides (paraquat)
3. Anticoagulant rodenticides.(warfarin related agents)

Front 57

Warfarin is commonly known as

Back 57

Rat Poison

Front 58

Warfarin is commonly found in what commercial substance?

Back 58

Commercial rodenticides

Front 59

How does warfarin disrupt us specifically? Aka, describe the mechanism:

Back 59

well its important to understand that Vitamin K is an important is required for the maturation of clotting factors (prothrombins). In the process, Vitamin K is oxidized to Vitamin K epoxide, and then it is reduced back to Vitamin K. DUE to the structural similarity between vitamin K and warfarin, warfarin blocks the binding of V-K to its reductase and thus prevents maturation of coagulant factors. This results in uncontrolled bleeding and death

Front 60

How did a resistance come about in rats to beat the danger of warfarin? What was done to overcome this resistance?

Back 60

A mutation in Vitamin K Epoxide Reductase occured, resisting the blockage by Warfarin.
Superwarfarin was developed, (much more potent than warfarin)

Front 61

What is paraquat?

Back 61

A pesticide. Bypyridal class of herbicides

Front 62

Dangers of paraquat?

Back 62

Reported to cause accidental or suicidal fatality
2. Damages lung, kidney, liver

Pulmonary fibrosis is usually the cause of death!

Front 63

Mechanism of paraquat

Back 63

Induces the generation of super oxide radicals from oxygen--> induces lipid peroxidation --> damages cell membranes and enzymes --> tissue damage --> Pulmonary Fibrosis -->Eventual delayed death due to respiratory distress

Front 64

Treatment for Paraquat Poisoning: ?
What should not be given for treatment:?

Back 64

1. REmoval of unabsorbed paraquat by gastric lavage or activated charcoal
2. REmoval of absorbed paraquat by hemodialysis, hemoperfusion, serial activated charcoal
DO NOT TREAT WITH: 100% oxygen. This actually enhances paraquat toxicity

Front 65

What are the three classes of pesticides?

Back 65

1. Chlorinated Aromatic Hydrocarbons (dioxin)
2. Bipyridal class of herbicides (paraquat)
3. Anticoagulant rodenticides.(warfarin related agents)

Front 66

What is warfarin?

Back 66

Rat Poison

Front 67

What class of pesticide does it fall in?

Back 67

Anticoagulant Rodenticide

Front 68

Warfarin is structurally similar to :?

Back 68

Vitamin K

Front 69

What is the danger of warfarin based pesticides?

Back 69

Uncontrolled bleeding and death

Front 70

What is the mechanism of action of warfarin?

Back 70

Well , V-K is required for the maturation of coagulant factors in the blood (prothrombins). Usually, V-K is oxidized to VK epoxide and then it is reduced back to VK. Warfarin, blocks the reductase action since it is SO structurally similar to VK. Thus is prevents maturation of coagulant factors, leading to bleeding and death.

Front 71

What resistance to warfarin has developed in rats? What has this lead to?

Back 71

Rats have developed a resistance to warfarin through a mutation in VK epoxide reductase. This has lead to the development of superwarfarin which is 100X more portent and has a longer half life.

Front 72

What are the clinical presentations of anticoagulant rodenticides (warfarin)

Back 72

GI bleeding(melena), hematuria, epitaxis, multiple ecchymotic lesions

Front 73

Treatments to warfarin toxification include:(3)
Treatment if bleeding is heavy and serious:?

Back 73

1. Antidote: V-K is administered as it will compete with warfarin for binding to VK epoxide reductase.. In cases where warfarin was taken in, VK is administered for a few ways. In cases with superwarfarin, VK is administered for a few months
2. Activated charcoal is given to eliminate warfarin from the gut
3. Cholestyramine binds directly to warfarin is orally administered to stop enterohepatic recirculation.

Intense Bleeding: Fresh frozen plasma or factor IX (has prothrombins)

Front 74

What is the overall three step strategy in treating a poisoned patient?

Back 74

1 Gut Decontamination (before toxin is absorbed)
2.Enhancing Elimination of toxin (after toxin is absorbed)
3. Use specific antidotes and other supportive therapy

Front 75

What are the three strategies for gut decontamination?
When is gut decontamination useful?

Back 75

1 Emesis (induced vomiting),
2 Gastric Lavage (washing out),
3 Activated Charcoal (it can adsorb many drugs and toxins)

Useful within one hour of toxin ingestion; before the toxin is absorbed!

Front 76

What are strategies of Enhancing elimination of toxins?

Back 76

1. Hemodialysis: blood is pumped through a permeable membrane, but cells and proteins stay in. Toxin must be permeable and pumped out.
2. Hemoperfusion:Blood is pumped through a cartridge of charcoal and then pumped back into the blood stream. Unlike hemodialysis, there is no molecular weight limiting factor
3. Activated Charcoal:Even after the absorption of toxin, activated charcoal is administered to remove toxins that are secreted into the gut.

Front 77

Why is activated charcoal useful after the absorption of toxin has already occured?
Give some examples of toxins it is useful for?

Back 77

Even after the absorption of toxin, activated charcoal is administered to remove toxins that are secreted into the gut.
It is also effective in removing toxins that are subject to enterohepatic or enteroenteric recirculation.
egs: CAHs, paraquat

Front 78

Hemodialysis is limited by the fact that is only good for toxins that ..

Back 78

have a molecular weight of less than 500, have a high water solubility, and have low protein binding ( because proteins are not filtered out)

Front 79

Hemoperfusion: if the cartridge used is charcoal, that is good to take out:...
if the cartridge is resin, that is good to take out..

Back 79

charcoal: polar and nonpolar drugs
resin: nonpolar drugs

Front 80

What are some advantages hemoperfusion has over hemodialysis?

Back 80

IT not limited by molecular weight, water solubility, or protein binding.

Front 81

General: several toxic agents cause metabolic acidosis. HOw?

Back 81

Well, toxins like (CO, cyanide, methanol, iron) interfere with the mitochondrial generation of ATP; and compensatory glycolysis produces lots of LACTIC ACID.

Front 82

General: Name antidotes that are used for many different toxins:

Back 82

1. Toxin: CO. Antidote: High Oxygen 100% administration. Oxygen competes with CO and displaces CO from hemoglobin
2. Toxin: Cyanide. Antidote: Methemoglobin. It indirectly competes for cytochrome oxidase; thiosulfate enhances elimination of cyanide
3. Toxin: Methanol. Antidote: Ethanol. It compete for alcohol dehydrogenase.
4. Toxin: Metals. Antidote: chelators. COmpete with proteins for toxic metal complexes,facilitate renal elimination of metals
5. Toxin: Warfari. Antidote: VK compete for binding site on VK epoxide reductase